Hyaluronan-Inorganic Nanohybrid Materials for Biomedical Applications

Review pubs.acs.org/Biomac

Hyaluronan-Inorganic Nanohybrid Materials for Biomedical Applications Zhixiang Cai,† Hongbin Zhang,*,† Yue Wei,† and Fengsong Cong‡ †

Department of Polymer Science and Engineering, School of Chemistry and Chemical Engineering and ‡Department of Biochemistry and Molecular Biology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China ABSTRACT: Nanomaterials, including gold, silver, and magnetic nanoparticles, carbon, and mesoporous materials, possess unique physiochemical and biological properties, thus offering promising applications in biomedicine, such as in drug delivery, biosensing, molecular imaging, and therapy. Recent advances in nanotechnology have improved the features and properties of nanomaterials. However, these nanomaterials are potentially cytotoxic and demonstrate a lack of cell-specific function. Thus, they have been functionalized with various polymers, especially polysaccharides, to reduce toxicity and improve biocompatibility and stability under physiological conditions. In particular, nanomaterials have been widely functionalized with hyaluronan (HA) to enhance their distribution in specific cells and tissues. This review highlights the most recent advances on HAfunctionalized nanomaterials for biotechnological and biomedical applications, as nanocarriers in drug delivery, contrast agents in molecular imaging, and diagnostic agents in cancer therapy. A critical evaluation of barriers affecting the use of HA-functionalized nanomaterials is also discussed, and insights into the outlook of the field are explored. for further chemical modifications.14 At the molecular level, HA interacts with cell surface receptors, such as CD44, RHAMM, and LYVE-1 receptors, collectively known as hyaladherins, which are overexpressed in many cancer cells. Thus, HA is used as a diagnostic indicator of cancerous angiogenesis and progression of various tumor types.15,16 Moreover, HA exhibits excellent physiochemical properties, such as biodegradability, cytocompatibility, nontoxicity, nonimmunogenicity, and high water-binding capacity.17 The physiochemical properties and multifaceted biological functions of HA have attracted considerable attention for the development of HA-based biomaterials for various biomedical applications,18 such as drug delivery,19,20 targeted diagnosis,21 tissue engineering,22 and molecular imaging.23 Successful advances in nanotechnology have contributed to progress in the development of HA-functionalized nanomaterials (HA-nanomaterials) that are used in biological applications. Moreover, the intriguing biological properties of HA render HA a potential targeting ligand in nanoparticle modification. Various nanomaterials, such as gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs),24,25 carbon materials (graphene, carbon nanotubes (CNTs), and quantum dots (QDs)),26,27 magnetic iron oxides,21 and mesoporous materials,28 have been functionalized with HA. HA-based nanomaterials are multifunctional nanomaterials that combine the physical and chemical properties of nanomaterials with the

1. INTRODUCTION Nanotechnology is a multidisciplinary field involving the fabrication and utilization of materials, devices, or systems at the nanoscale.1 Advances in nanotechnology have led to the development of nanomaterials whose size, geometry, and surface functionality can be controlled at the nanoscale.2 The development of nanotechnology-based materials has boomed in the past few decades because nanomaterials are unique in that their sizes and physical properties are chemically tunable. In addition, they are expected to be useful in innovations, and they play critical roles in various biomedical applications.3−5 However, unfunctionalized nanomaterials are potentially cytotoxic and lack cell-specific function.6 Thus, the fabrication of nanomaterials functionalized with biological molecules and carbohydrates and their applications has sharply increased in recent years.7−9 Hyaluronan or hyaluronic acid (HA) is a naturally occurring linear polysaccharide consisting of repeating units of Dglucuronic acid and N-acetyl glycosamine alternately linked by β-(1,4) and β-(1,3) glycosidic bonds; as one of the most important and ubiquitous glycosaminoglycans, HA is distributed widely in the human body, such as in vitreous of the eye and in the extracellular matrix of cartilage tissues.10 The function of HA in vivo is to maintain moisture, adjust osmotic pressure, lubricate joints, and absorb shock, all of which are closely related to its physiochemical and rheological properties. In a series of works by our group, the physiochemical and rheological properties of HA have been investigated.11−13 In addition, HA bears functional groups including hydroxyl carboxylic groups and an N-acetyl group, which can be utilized © 2017 American Chemical Society

Received: March 24, 2017 Revised: May 4, 2017 Published: May 9, 2017 1677

DOI: 10.1021/acs.biomac.7b00424 Biomacromolecules 2017, 18, 1677−1696

Review

Biomacromolecules biological characteristics of HA. This review focuses on recent progress in the development of HA-nanomaterials and their applications in biomedicine. HA-nanomaterials are likely to open new opportunities for rapid expansion of the biomedical applications of nanomaterials.

2. HA-FUNCTIONALIZED NANOMATERIALS (HA-NANOMATERIALS) 2.1. HA-Functionalized Au Nanocomposites. Au nanocomposites display biological inertness and possess distinct physical and chemical attributes, including controlled geometrical, optical, and surface chemical properties. Au nanocomposites are useful in a variety of biomedical applications because the surfaces of Au nanocomposites can be modified, allowing their attachment to a ligand, drug, or other target biomolecules. These features of Au nanocomposites have recently led to new and exciting developments that present enormous potential applications in biology and medicine.29 This development was first fully realized in a range of medical diagnostic and therapeutic applications.30 In this section, we will briefly describe the synthesis of HA-functionalized Au nanocomposites and highlight their applications in biomedical fields. Considerable efforts have been devoted to developing AuNPs with monodispersity and controlled size. Nanoparticles are defined as particulate dispersions or solid particles with a size generally in the range of 1−100 nm.31,32 The development of nontoxic and eco-friendly processes of AuNP synthesis has become a challenging issue for many researchers. These days, researchers have been inspired to integrate “green chemistry” approaches to fabricate AuNPs using biopolymers.33 In particular, AuNPs were prepared by reducing AuCl4 using HA as both the reducing and stabilizing agent.34 AuNPs are considerably more stable than naked AuNPs under physiological conditions because HA bound to nanoparticles causes electrostatic repulsion. Apart from their unique physical attributes, AuNPs can be potentially applied in biomedical fields given the excellent physical properties (optical and electrical) of AuNPs and the biological activities of HA. Hien and co-workers have developed a method to synthesize HAcapped AuNPs by using a γ-irradiation method.35 Their results showed that the AuNPs exhibited narrow size distribution under high dose rate and HA concentrations, whereas they displayed a wide size distribution under high Au3+ concentrations. The HA-capped AuNPs smaller than 10 nm can be potentially applied in biomedicines and cosmetics. Li and co-workers19 have recently developed an HA-Au supramolecular conjugate (HACD-AuNPs) by using AuNPs bearing adamantane moieties and cyclodextrin-grafted HA (Figure 1). This supramolecular conjugate can be stably constructed because of the high affinity between the βcyclodextrin (β-CD) cavity and adamantane moieties. The supramolecular conjugate was subsequently explored as an efficient targeted delivery system for various anticancer drugs, such as doxorubicin hydrochloride (DOX), paclitaxel, camptothecin (CPT), irinotecan hydrochloride (CPT-11), and topotecan hydrochloride (TPT). Taking the anticancer drug DOX for example, in vitro studies have shown that the DOX-loaded HACD-AuNPs delivery system exhibited high cellular uptake and anticancer activities that are comparable to those of free DOX but with low side effects owing to CD44 receptormediated endocytosis. Furthermore, the drug-loaded delivery system exhibited pH-responsive release under a mildly acidic

Figure 1. Schematic of the chemical structures and the construction of HACD-AuNPs and drug-loaded HACD-AuNPs: the drug delivery system containing CD-modified HA (HACD), AuNPs bearing adamantane moieties, and an anticancer drug. Reprinted by permission from Macmillan Publishers Ltd.: Scientific Reports, ref 19; Copyright 2014. http://www.nature.com/srep/.

environment, such as the internal environment of a cancer cell. To sum up, this smart HACD-AuNP supramolecular conjugate provides a versatile platform for targeted drug delivery characterized by high activity and low toxicity and suggests promising application for the clinical treatment of cancer. In this study, the average diameter of HACD-AuNPs was approximately 258 nm with a narrow size distribution. However, the most efficient cellular uptake was observed with particles ranging from 20 to 50 nm via the enhanced permeation and retention (EPR) effect.36 Therefore, the HACD-AuNP arrived at the diseased tissues through HAspecific recognition by cell surface receptors (CD44). In another study, AuNPs have been actively used as a delivery carrier for various biopharmaceuticals.37 In addition to its application in the delivery of anticancer drugs, AuNPs have been proposed as carriers in the target-specific systemic treatment of hepatitis C virus (HCV) infection. Lee and coworkers developed a target-specific long-acting delivery system (HA-AuNPs/IFNα complex) based on interferon α (IFNα) loaded on thiolated HA-modified AuNPs (HA-AuNPs). The HA-AuNPs/IFNα complex has some advantages such as enhanced serum stability in human serum and target-specific delivery capacity in liver tissue. Overall, the HA-AuNPs/IFNα complex is a potential new nanomedicine that demonstrates an enhanced and prolonged efficacy for the treatment of chronic HCV infection, and this finding provides new insights into the development of drug release systems to treat HCV infection. AuNPs have been widely used in various visualization and bioimaging techniques to identify chemical and biological agents.38 Reactive oxygen species (ROS) are oxygen-containing molecules bearing an unpaired electron that are highly reactive in redox reactions. Studies have shown that ROS serve as signaling molecules regulating numerous cellular process, including proliferation. It is known that ROS generated beyond the limit of the natural antioxidant defense systems are considered toxic and can damage cellular macromolecules, resulting in cell death.39 To evaluate ROS toxicity, Lee and coworkers have demonstrated the use of novel and biocompatible ROS-sensitive AuNPs to detect the level of intracellular ROS 1678


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and chemo-photothermal synergistic effects present a significant potential application in cancer therapy. Au nanostructures have been intensively investigated because of their fascinating surface plasmon resonance (SPR) properties. The SPR properties are strongly dependent on the size, shape, and surface functionality of the Au nanostructures. NIRabsorbing Au nanorods functionalized with a biopolymeric shell and embedded in HA were recently prepared and used in carotid artery closure in vivo.43 Given that the hybrid material was rendered stable by HA, it can be easily stored because minimal optical and structural modifications occur over time. Overall, this work can open a new field in nanotechnologybased therapies employed in minimally invasive procedures in clinical practice. In addition, Liu and co-workers24 have reported on HA grafted onto the Au surface to fabricate an HA-Au sensor chip, which demonstrates excellent antifouling performance against protein adsorption and good stability and compatibility. SPR spectroscopy, which is a powerful tool used to monitor molecular interactions, was used in this study to investigate nonspecific adsorption onto materials ranging from single protein solutions and complex media to HA-Au biosensor chips. The results showed that the developed HAAu could be used to fabricate antifouling surfaces and SPR biosensor chips for sensitive detection of bovine serum albumin (BSA) and may be used in minimally invasive clinical practices. The HA-AuNPs nanomaterials for biomedical applications are summarized in Table 1. As mentioned-above, HA-functionalized AuNPs have been successfully applied in biomedical field as promising candidates for drug delivery systems and platforms for the detection of biological molecules. The motivations for AuNPs functionalized by HA are the enhanced targeting and delivery of drug to target cells and the reduced toxicity of AuNPs. However, despite reports that HA-AuNPs used in many medical and healthrelated conditions are inherently nontoxic, the efficacy, potential toxicity, and health impact of HA-AuNPs are still under some scrutiny. The challenge will be the preparation of a range of HA-AuNP nanomaterials using a common synthetic strategy with exact surface functionality for accurate comparison. Further work is still needed to clarify their efficacy and safety when taking advantage of the biological properties of HA and the unique physiochemical properties of AuNPs to fabricate HA-AuNPs especially for biological imaging, drug delivery, and cancer treatment. 2.2. HA-Functionalized Ag Nanocomposites. Ag nanostructures have been attracting interest because of their numerous potential applications in surface-enhanced Raman scattering (SERS),44 catalysis,45 and biosensing.46 AgNPs exhibit exceptional antibacterial properties and thus present potential biological and medical applications.47 In recent years, Ag-based biomedical products are increasingly being utilized in bioactive materials, demonstrating their capability to effectively retard and prevent bacterial infections. Various approaches for AgNP fabrication have been developed in the past few decades. However, with increasing awareness on environmental protection, carbohydrate polymers have been employed as reducing and stabilizing agents in AgNP synthesis to avoid the use of the conventional noxious reducing and stabilizing agents. HA has been employed as a template to direct AgNP synthesis. Some typical methods for AgNP synthesis and recent applications of AgNPs are introduced. For instance, Cui and co-workers have utilized HA to prepare different Ag nanostructures for SERS application.48 These

induced by various polystyrene (PS) nanoparticles with different sizes and functional groups.40 The ROS-sensitive AuNPs (HF-AuNPs) were successfully prepared using fluorescent dye-labeled HA grafted onto the surface of AuNPs. The HF-AuNPs possessed enhanced detection sensitivity for intracellular ROS relative to that for other commercialized ROS fluorescent probes. The results revealed that smaller and more positively charged PS nanoparticles highly induced intracellular ROS generation, confirming the high cellular toxicity of these particles. Furthermore, Hyun et al.41 have designed ROS-sensitive Au nanoprobes (HHAuNPs) by using near-infrared (NIR) fluorescence dye-labeled HA and AuNPs for ischemic brain imaging. The HHAuNPs nanoparticles exhibited high stability in a wide range of pH, salt concentrations, and media and possessed a strong fluorescence signal. This study demonstrated that the HHAuNPs are a powerful tool to monitor ROS level and identify infarct areas in ischemic brain for stroke treatment. In addition to the use of colloidal Au-containing spherical particles, the use of nonspherical cylindrical particles (nanorods), nanoshells, nanocages, and nanostars has been studied, and these particles are widely applied in current medical and biological research. For example, HA-capped Au nanocages (AuNCs-HA) were used to design a multistimuli-responsive platform for targeted, noninvasive, and pinpointed intracellular DOX release (Figure 2).42 Drug-loaded nanohybrids were

Figure 2. Schematic of a multistimuli-responsive platform based on DOX-loaded AuNCs-HA nanoparticles for pinpointed intracellular drug release and synergistic therapy: a pH and NIR stimuli-responsive targeted drug delivery system was activated to trigger the release of encapsulated drug after nanoparticles were internalized. Reprinted from ref 42; Copyright 2014, with permission from Elsevier.

taken up efficiently by cancer cells via HA-CD44 interactions and subsequently degraded intracellularly into small fragments, facilitating DOX release. In vivo experiments have further revealed that NIR irradiation enhances the release of encapsulated drug and improves its therapeutic efficacy because of the excellent photothermal properties of the drug. In particular, one of the major features of AuNCs-HA is the combination of chemotherapy and photothermal therapy that can result in an excellent synergistic effect. Thus, AuNCs-HA nanohybrids demonstrated biocompatibility, CD44-targetability, multistimuli responsiveness, and pinpointed drug release, 1679


nanocages Au substrate nanoshell

∼50 10.5 105 238−248

100

1000, 350 35

6

1680

305.5 ± 15.1

100

22

HA-coated AgNPs

13.5

none

1750

nanoshell

nanoshell

fiber

nanoshell

6.0 ± 0.7

not given

HA fibers with incorporated AgNPs (HA-Ag NPs) HA-coated AgNPs

nanorod

91.28

10

HA-gold nanorod/death receptor 5 antibody (HA-AuNR/DR5 Ab) complex FITC-HA functionalized AuNPs

nanoparticle

150.2 ± 3.1

12

nanoshell

55.9 ± 3.1

1−4

supramolecular conjugates

258

46

nanoshell

nanoshell nanoshell

nanoshell

29.25 ∼20

4−10

nanomaterials shape

not given 12 17

nanomaterial dimensions (nm)

AuNP-HA nanoassembly

CD-modified HA-AuNP supramolecular conjugates (HACDAuNPs) HA immobilized on the surface of AuNPs

HA-stabilized iodine-containing nanoparticles with Au nanoshell HA-modifed manganese-chelated dendrimer-entrapped AuNPs

HA-AuNP/interferon α complex Fluorescein-labeled HA immobilized on AuNPs (HHAuNPs) drug-loaded gold nanocages @ HA (AuNCs-HA) HA onto Au substrate

HA-capped AuNPs

system

Mw of HA (kDa) drug

none

none

none

none

photodynamic therapy death receptor 5 antibody

DOX, PTX, CPT, CPT-11, and TPT none

photothermal ablation none

none

DOX

interferon α none

none

properties

ultrasmall and monodisperse; excellent long-term stability and low cytotoxicity

high cell uptake and anticancer activities

high antibacterial activity; low cytotoxicity

sensitive, rapid, and accurate analysis of HAase

biostable, photo- and enzyme-activatable nanomaterial photoacoustic imaging and antibody cancer therapy

cellular probe; photodamage media

excellent dispersibility and stability; multifunctional good stability and dispersibility; high X-ray attenuation intensity and favorable r1 relaxivity high cellular uptake and anticancer activities; low side effects

combination of chemotherapy and photothermal therapy high stability and antifouling performance

high stability and target specificity high stability and strong fluorescence signal

monodispersity

Table 1. Major Nanomaterials of HA-AuNPs and HA-AgNPs for Biomedical Applications applications

nanoplatform for X-ray CT and SPECT imaging

AgNP-mediated cancer treatment

accurate detection of HAase for clinical diagnosis of HAase-related diseases, such as bladder cancer antibacterial activity and cell viability

photothermally boosted photodynamic tumor ablation novel theranostic platform for noninvasive transdermal treatment of skin cancers

mediator of laser-induced photothermal cell damage

versatile platform for the targeted delivery of anticancer drugs

treatment of HCV infection nanoprobes for reactive oxygen species detection and treatment of stroke multistimuli-responsive intracellular drug release systems for synergistic cancer therapy resist nonspecific adsorption from complex media in SPR biosensors X-ray CT imaging and photothermal therapy of tumors CT/magnetic resonance (MR) dual-mode imaging

biomedicines and cosmetics

tumor or cell models

mouse fibroblast cell line 3T3 MCF-7 and SW480 cells Lewis lung carcinoma

none

HCT116 cancer cells

MDA-MB-435 S, MDA-MB-453, and NIH/3T3 MDA-MB-231 cells

MCF-7 cells

hepatocellular carcinoma (HCCLM3 cells)

MCF-7

MDA-MB-231 and NIH-3T3 cells none

none none

none

60

59

54

67

66

65

64

19

63

62

24

42

37 41,61

35

ref

Biomacromolecules Review


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further developed by Zhang et al.60 Because of the novel physiochemical and optical properties of AgNPs, HA-AgNPs were first developed as a nanoplatform for X-ray computed tomography (CT) and single-photon emission computed tomography (SPECT) imaging. Furthermore, the obtained HA-AgNPs were spherical, ultrasmall, and monodisperse and demonstrated excellent long-term stability and low cytotoxicity. This study clearly demonstrated the greater potential for in vivo applications (Figure 3). As a matter of course, further evidence is needed to adequately assess the long-term toxicity of HAAgNP exposure on human physiology.

studies have shown that the shape of Ag nanostructrues could be easily controlled by the storage time of HA and AgNO3 solution before being mixed for photoreduction. Application of a Ag nanoplate has improved SERS efficiency compared with the application of Ag spherical NPs because SERS efficiency greatly depends on particle shape and irradiation time. By contrast, Xia and co-workers49 have utilized HA to prepare Ag nanostructures that present potential applications in SERS and biosensing. In addition, Kemp et al.34,50 have studied the antibacterial, anticoagulant, and anti-inflammatory efficacies of AgNPs stabilized by HA. The results demonstrated that these nanoparticles exhibit a unique antibacterial property and high anticoagulant and anti-inflammatory efficiencies, which are useful in various biological and biomedical applications. The number of HA-based nanocomposites has increased in the past decade. In addition to preparing AgNPs using HA, incorporation of AgNPs into HA has recently become a research hotspot because of the outstanding physical, chemical, and biological properties of HA and AgNPs. For example, Chen and co-workers51 took advantage of these properties to synthesize core−sheath electrospun HA/polycaprolactone nanofibrous membranes embedded with AgNPs; this complex is used to prevent peritendinous adhesion. The HA and AgNPs in this nanofibrous membrane were used for effective lubrication and antibacterial activity, respectively. The in vitro and in vivo experiments further confirmed that this nanofibrous membrane reduces peritendinous adhesion and proliferation without exerting significant cytotoxicity. In addition, Cui and co-workers52 developed AgNPs embedded in a layer-by-layer assembled HA/poly(dimethyldiallylammonium chloride) (PDDA) structure. This nanomaterial has good stability for a localized SPR biosensor and excellent antibacterial capability, indicating that the film offers practical potential application as a biosensing and antimicrobial material. Encouraged by this result, Zhang et al.53 constructed an HA-AgNP-hemoglobin multilayer composite film with good biocompatibility, antibacterial, and stability properties and subsequently investigated its electrocatalytic properties. The results showed that this film presents a significant potential use in biosensing. Zhang and coworkers25 subsequently described a complex hydrogel formed from HA and PVA and embedded with AgNPs; this hydrogel displayed a high antibacterial property and can potentially be used as a wound dressing material. Moreover, studies have reported on nanocomposites based on HA and AgNPs, and these nanocomposites demonstrate good biomedical activity.47,54−56 The majority of these studies have focused on the antibacterial property of HA-Ag nanocomposites. Earlier studies of biological applications for AgNPs focused mainly on the antibacterial issue. Recently, AgNPs have been reported for their potent antitumor activities owing to a possible mechanism of intracellular induction of ROS resulting in DNA damage.57 However, the nonspecific delivery and poor cellular uptake have significantly limited AgNPs used in the nanomedicine field. Moreover, they also have poor stability and relatively high cytotoxicity. For these limitations to be overcome, coated or functionalized AgNPs with biopolymers are required.58 In a study by Liang and co-workers,59 AgNPs were synthesized using HA, which acts as a reducing agent and stabilizer as well as targeting ligand. The antitumor efficacy of HA-AgNPs was significantly enhanced in comparison with that of the unmodified AgNPs, which can be attributed to CD44mediated endocytosis. The work was possibly the first to report targeted antitumor efficacy based on AgNPs. This idea was

Figure 3. Schematic of HA-coated AgNPs as a nanoplatform for in vivo imaging applications: the HA-AgNPs were used as a nanoplatform for X-ray CT and SPECT imaging after being radiolabeled with 99mTc. Reprinted from ref 60; Copyright 2016, American Chemical Society.

The HA-AgNP nanomaterials for biomedical applications are also summarized in Table 1. In conclusion, AgNPs are increasingly utilized in HA-based biomatials, which are proven to be very effective in retarding and preventing bacterial infections. However, there is still a large amount of development required for drug delivery systems and in vivo bioimaging applications. As already stated, although these studies have demonstrated that the HA/AgNPs have low-toxicity, numerous in vitro studies of AgNPs have shown long-term toxic effects to cell exposure on human physiology. Thus, the health impact of AgNPs will require researchers to be careful in the design AgNP-based nanomaterials. 2.3. HA-Functionalized Graphene (HA-Graphene) and Its Derivatives. Studies have recently focused on the development of graphene-based nanomaterials as new materials to be used in biomedical fields (mainly explored for their application in drug delivery, biosensing, and molecular imaging) because graphene possesses unique and extraordinary mechanical, thermal, chemical, and optical properties.68−71 However, the instability of graphene-based nanomaterials under physiological conditions has hindered their wide application. Therefore, a number of strategies have been developed to improve the physiological stability of graphene-based nanomaterials, among which HA-graphene and its derivatives have attracted significant attention. To address this problem of instability, we recently prepared pyrene-conjugated HA (HAPy) to facilitate the exfoliation and stabilization of laminar materials including graphene, hexagonal boron nitride, molybdenum disulfide, and CNTs in water under sonication.72 Moreover, the HA-Py conjugate that stabilizes the reduced graphene oxide (rGO) to be used in fabricating composite nanomaterials involving noble metals (Au, Ag, Pd, and Pt) was 1681


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Biomacromolecules further investigated.73 HA-Py is not only a stabilizing agent in this system but also facilitates and controls the decoration of metals on HA-Py-rGO. The Au-HA-Py-rGO hybrid nanomaterials also exhibited a high electrochemical/catalytic activity. Therefore, the hybrid nanocomposites can be employed as a sensing material for a wide range of biomedical and pharmaceutical applications. Overall, gaining a stable and biocompatible graphene remains challenging. In recent decades, investigators have found that graphene and GO are toxic to biological systems, greatly hindering their wide applications in the biomedical field.74 Therefore, surface functionalization of graphene and its derivatives is a crucial step. Given the versatile surface functionalization and ultrahigh surface area of graphene and its derivatives, these materials can be easily modified and functionalized with biomolecules to obtain graphene-based nanomaterials to be used in biomedical applications.75 In general, the cellular environment in tumor tissue is more acidic than in normal tissues.76 The application of graphene and its derivatives applied in drug delivery systems has been reported in the past few decades; π−π interactions become weaker in an acidic environment, resulting in pHresponsive drug release.77 This section presents the combination of HA with graphene-based nanomaterials for biomedical applications. Several reports have described the combination of HA with graphene-based nanomaterials for drug delivery. Miao and coworkers have recently prepared an HA-coated rGO used to construct a targeted anticancer drug delivery system.78 They first prepared cholesteryl-modified HA (CHA), which they used to coat rGO nanosheets to form CHA-rGO nanohybrid as nanoplatform for DOX loading. The CHA-rGO nanohybrid showed increased colloidal stability under physiological conditions and improved in vivo safety compared to that of rGO. A DOX-loaded CHA-rGO nanohybrid displayed increased antitumor efficacy compared with those of free DOX or rGO/DOX because of the high distribution and prolonged retention of CHA-rGO/DOX in tumor sites. Wu and co-workers subsequently prepared HA-conjugated GO for the development of a drug delivery system (Figure 4).79 The GO-HA showed negligible hemolytic activity and low cytotoxicity. The resulting DOX-loaded GO-HA exhibited high efficiency in targeted drug delivery in HeLa cells and can potentially inhibit tumor growth. Considerable efforts have been devoted to exploring graphene-based stimuli-responsive controlled drug delivery systems (CDDSs) by taking advantage of the acidic tumor microenvironment and high intracellular GSH levels in tumors. In a work related to GO-based CDDSs, HA-decorated GO nanohybrids were used in loading anticancer drug (DOX) (HA-GO-DOX) to fabricate a pH-dependent drug release system.80 Owing to the aromatic structure of DOX and GO, DOX can be loaded into a GO nanostructure via π−π stacking (Figure 5). HA-GO-DOX exhibited superior physiological stability and possessed high drug loading capacity and drug delivery efficiency. As a result, HA-GO-DOX demonstrated higher tumor inhibition toward H22 hepatic cancer cells than those of free DOX and GO-DOX under the pH of the tumor micoenvironment. Therefore, pH-responsive HA-GO-DOX is a promising agent for enhancing the antitumor efficacy of conventional chemotherapy against cancer. In a follow up study, Jung et al. synthesized a targeted anticancer drug delivery system based on HA and GO.81 They found that the nanocarrier demonstrated not only enhanced serum stability

Figure 4. Schematic of the preparation of DOX-loaded GO-HA: (A) adipic acid dihydrazide (ADH)-functionalized GO (GO-ADH), (B) HA-conjugated GO-ADH (GO-HA), (C) DOX loaded onto GO-HA, and (D) intravenous administration of GO-HA/DOX. Reprinted from ref 79; Copyright 2013, with permission from Elsevier.

Figure 5. Schematic of the preparation of HA-GO-DOX nanohybrid: HA-ADH as both targeting and hydrophilic moieties, functionalized GO, and DOX nanocomposite formed by π−π stacking. Reprinted from ref 80; Copyright 2014, American Chemical Society.

and targeted specific anticancer drug delivery but also the ability for pH-responsive drug release. As mentioned above, the as-obtained nanocarrier can serve as an effective synergistic anticancer drug delivery system. Graphene-based nanomaterials have also been developed for photothermal treatment (PTT) of cancer under low-power NIR irradiation because of their excellent light-to-heat conversion. A considerable number of studies have developed HA-graphene-based nanomaterials as targetable and photoactivity switchable nanoplatforms for PTT of cancer. Khatun and co-workers recently reported on DOX-conjugated graphene in a sulfide bond-linked HA nanogel, which was used as drug carrier for targeted drug delivery that demonstrates light- and pH-responsive release.69 This nanogel showed good monodispersibility and stability in buffer and serum and possessed an excellent photoluminescence property. Their results showed that the responsiveness of the nanohybrid to pH changes in the cancer microenvironment triggered DOX release and effectively inhibited growth of the A549 cell line; thus, this nanohybrid is potentially useful for constructing 1682


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contrast agent as well as a heat source when excited by laser irradiation. Although graphene derivatives have been increasingly investigated in the bioimaging field, to the best of our knowledge, in most previous reports more attention has been paid to utilizing organic fluorescent dye-functionalized graphene derivatives for in vitro and in vivo fluorescence imaging.75 It is worth noting that all of these HA-functionalized graphene and derivative nanomaterials are prepared by coupling via N-ethyl-N′-dimethylaminopropyl-carbodiimide (EDC) and N-hydroxysuccinimide (NHS) chemistry. Indeed, hybrid nanomaterials with various functionalities prepared via EDC/NHS chemistry have been extensively reported. This method offers some advantages for the simplicity of preparation and manipulation. HA-graphene and its derivatives for biomedical applications are summarized in Table 2. Overall, owing to their excellent physiochemical properties and biocompatibility, these nanocarriers of HA-graphene and its derivatives are promising candidates as multifunctional nanoplatforms that combine both therapeutic components and multimodal imaging. These nanoplatforms can bypass many biological barriers to enhance targeting efficacy. However, there are a few major obstacles in the biomedical application of graphene-based nanomaterials, i.e., the nonbiodegradable nature and long-term toxicity of graphene and its derivatives, even modified by HA. In addition, the in vivo behavior of HAgraphene nanomaterials with different structures, sizes, and surface properties remains unknown. At the same time, HAgraphene nanomaterials are difficult and expensive to manufacture at large scales with optimal quality. Thus, significant study of HA-graphene and its derivatives is still needed before going to clinical trials. The future of HAgraphene and its derivatives utilized in biomedical fields looks brighter than ever, yet many obstacles remain to be overcome. 2.4. HA-Functionalized CNTs (HA-CNTs). CNTs have recently emerged as promising nanomaterials in nanomedicine, wherein they serve as drug delivery vehicles and bioimaging agents owing to their unique structure and properties, including high aspect ratio, unique optical property, high drug-loading capability, and enhanced cellular uptake.89,90 However, because of the very high long-range van der Waals forces of attraction, pristine CNTs are limited by technological barriers, such as high aggregation tendency and poor aqueous dispersibility, thereby limiting their applications in biomedicine.91 Furthermore, an issue worthy of consideration is that pristine CNTs are highly toxic when applied to in vitro and in vivo experiments.92 Thus, approaches must be developed to confer CNTs with improved water solubility and high biocompatibility and reduce their systemic toxicity. In particular, covalent functionalization of CNTs is one of the most powerful approaches to render CNTs with these properties.93 HA has been used for targeted cancer therapy owing to its unique and excellent biological properties. Thus, HA-CNTs are promising tumor-targeting drug delivery agents for cancer treatment. Moreover, recent expansion in HA-CNTs, along with the identification of disease-specific molecular target and imaging capabilities, has promoted the development of multifunctional, drug-loaded CNTs.27,94−96 This section presents the latest achievements in the development of HA-CNTs used for biomedical applications. A considerable number of works have prepared HAconjugated CNTs, generating new nanomaterials for delivery of insoluble anticancer drugs. For example, Yao and co-

stimuli-responsive drug release matrices. Jung and co-workers investigated graphene oxide-HA conjugate (GO-HA) for photothermal ablation therapy of melanoma skin cancer using an NIR laser (Figure 6).82 This kind of nanohyrid material

Figure 6. Schematic of targeted delivery of GO-HA and photothermal ablation: transdermal delivery of GO-HA into melanoma skin cancer cells and the subsequent photothermal ablation therapy using NIR irradiation. Reprinted from ref 82; Copyright 2014, American Chemical Society.

exhibited high light-to-heat conversion efficiency and low cytotoxicity. After NIR irradiation, tumor tissues were completely ablated without recurrence of tumorigenesis. This intriguing result revealed that this system is apparently useful as a therapeutic agent for transdermal chemotherapy and PTT of melanoma skin cancers. Insufficient visualization of the delivery, distribution, metabolism, and digestion of PTT has seriously restricted the wide application of PTT in the biomedical field. Therefore, the development of different imaging-guided PTT nanoplatforms is necessary. To address this issue, researchers have exerted considerable effort toward exploring imaging-guided PTT nanoplatforms that demonstrate powerful imaging and therapeutic capacities, and considerable achievements have been achieved over the past few years. For example, Miao et al. have reported a photoresponsive NIR imaging agent (indocyanine green, ICG) loaded onto HA-conjugated rGO (HArGO) that can be utilized as an image-guided synergistic antitumor PTT.83 Compared with the photostability of free ICG, that of ICG-containing HA-rGO or rGO was substantially enhanced. In this system, the ICG-loaded HA-rGO nanohybrid material had high photostability and photothermal antitumor efficiency, which can be developed as a potential theranostic nanoplatform to track and monitor targeted drug as well as a synergistic photothermal antitumor therapy. A similar finding was reported by Li et al., wherein photosensitizers (chlorin Ce6) were effectively loaded onto the surface of HA-GO that had high colloidal stability and enhanced photodynamic efficiency, which was developed as a target and photoactivity switchable nanoplatform for photodynamic therapy (PDT).84 Graphene-based nanomaterials have also attracted significant interest in the area of bioimaging because they have been found to be photoluminescent in the visible and infrared regions.75,85 On the basis of their high intrinsic NIR absorbance, functionalized GO and rGO have been used for live cell imaging.86,87 In a recent study for this purpose, branched polyethylenimine (BPEI) conjugated to GO was designed to be used as a gene delivery vector and as a bioimaging tool because of its low cytotoxicity and high gene delivery efficiency.88 In another case, Khatun and co-workers combined HA with graphene to prepare a light- and pH-responsive drug release system useful for the delivery of DOX and killing tumor cells.69 Graphene in the nanomaterials acted as an optical imaging 1683


1684

DOX DOX

100

214

5.8

230

175− 350 9.6

GO-HA conjugate

GO-HA conjugate

ICG loaded onto HA-anchored rGO (HArGO) nanosheets photosensitizer (PS; Ce6)-loaded HAGO conjugate photochromic dye spiropyran (SP) HA (HA-SP)-functionalized rGO HA-modified multifunctional Qgraphene HA-decorated GO

folate-terminated PEG-modified HA (FA-PEG-HA) conjugated with CDs

DOX

none

none

not given not given 400

HA-QD conjugate (CdSe/CdS/ZnS)

DOX none

230 234

HA-GQD HA-5β-cholanic acid-functionalized SWCNTs HA-CQDs

none

PTT and PDT none

epirubicin (epi) salinomycin

DOX

2

>1000

not given 234

not given 17.5

DOX

nucleic acid

DOX

PTT

epirubicin

DOX

HA-Cdot conjugates

HA-SMWCNTs

istearoylphosphatidylethanolamine-HA (DSPE-HA) conjugated with SWNTs CHI-coated SWNTs loaded with SAL functionalized with HA ICG-HA-SWCNTs

MWCNT-HA conjugate

HA- and CHI-modified SWNTs

not given 0.006

PDT

100

HA-decorated GO

HA-conjugated GO

PTT

not given 3.5

HA-grafted GO

DOX

214

CHA-coated rGO nanosheets

DOX; thermotherapy DOX

7000

drug

graphene-DOX conjugate in HA nanogel

system

Mw of HA (kDa)

none

none

none

pH none

none

none

none

none

none

pH

pH

none

redox

none

none

none

none

none

pH

pH

none

none

light; pH

stimuli responsive

real-time and noninvasive location tracking to cancer cells

nontoxic, strong fluorescence high aqueous solubility, enhanced cell penetration, selective targeting uniform size-distribution, highly hydrophilic surface, superior fluorescence low cytotoxicity, biocompatibility, targetability

dtable dispersity, high biosafety, high delivery and antitumor efficiency enhanced cellular uptake and therapeutic efficiency favorable stability, biocompatibility, photothermal conversion efficiency reduced pulmonary toxicity potential of SMWCNs negligible cytotoxicity, strong fluorescence

high anticancer efficiency and fluorescence imaging enhanced biostability, high photothermal response fluorescence-switchable cancer theranostic system high water solubility, low toxicity, high therapeutic efficacy reduced drug-associated cardiotoxicity

enhanced colloidal stability and improved in vivo safety negligible hemolytic activity and low cytotoxicity superior physiological stability, high drug loading capacity and delivery efficiency enhanced serum stability, targeted specific anticancer drug delivery, pH-responsive release high light-to-heat conversion efficiency and low cytotoxicity high photostability and photothermal antitumor efficiency high colloidal stability and photodynamic efficiency nontoxic, high fluorescence signal

monodispersibility, good stability, excellent photoluminescence

properties

tumor model

dual receptor-mediated targeting tumor theranostics

novel cell-specific fluorescent probes for high CD44 expression in tumor-targeted imaging and labeling in vivo lymphatic vessel imaging

target-specific drug delivery carrier for the treatment of liver diseases and a promising bioimaging agent target delivery and cell imaging molecular imaging

promising carrier for drug delivery in multidrug resistance (MDR) cancers overcome the recurrence and metastasis of gastric cancer and improve gastric cancer treatment theranostic nanoparticle for CD44-targeted and image-guided dual PTT and PDT cancer therapy reduce pulmonary injury

A549 cells

“smart” platform for tumor-targeted delivery of anticancer agents.

HeLa cells, human dermal fibroblast (hDF) cells SKOV3 cells

HeLa cells

A549 cells SCC7 and 3T3 cells

B16F1 and HEK293 cells

human bronchial epithelial cells

SCC7 cells

gastric cancer stem cells

A549 cells

MBA-MB-231 cells HeLa cells

MDA-MB-231 cells

A549 and MRC-5 cells

A549 cells

human KB epidermal carcinoma cells HeLa cells

B16F1 melanoma cells

B16F1 melanoma cells

H22 hepatic cancer cells

HeLa and L929 cells

KB epidermal carcinoma cells

lung cancer cells (A549)

overcome multiple biological barriers resulting in specific and enhanced cancer treatment target breast cancer cells, visualize endogenous miR-21 and inhibit its tumorigenicity controlled release and targeted delivery to cancer cells

targeted killing of drug-resistant lung cancer cells

in vivo imaging and target delivery

theranostic nanoplatform for image-guided and synergistic photothermal antitumor therapy cancer-targeted photodynamic therapy

photothermal ablation therapy of skin cancer

system for DOX delivery to the tumors and to suppress tumor growth targeted and pH-responsive drug delivery system for controlling the release of DOX for tumor therapy pH-dependent drug release and target specific anticancer effect

tumor-targeting delivery system for anticancer agents

thermo and chemotherapeutic, real-time noninvasive imaging, and light-glutathione-responsive controlled drug release

applications

Table 2. Selected HA-Based Carbon Nanomaterials for Drug Delivery Systems, Bioimaging, and Tumor Theranostics

115

113

116

117 96

118

104

94

97

95

91

98

123

122

121

71

84

83

82

81

80

79

78

69

ref

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Biomacromolecules

novel drug delivery carriers for the treatment of various chronic liver diseases including hepatitis, liver cirrhosis, and liver cancer

112

ref

124

tumor model

MD-MB-231 and MCF-7 breast cancer cells hepatic stellate cells (HSC-T6) and hepatoma cells (HepG2) CD44+ cancer cell-targeted imaging

applications

significantly inhibited the migration and invasion of CSCs. Unlike pristine CNTs, HA-CNTs are stable in PBS and culture media. Similarly, Mo and co-workers98 have described a strategy to introduce DOX into HA and CHI-functionalized SWNTs (DOX-SWNTs-CHI-HA), which displayed high water solubility, low toxicity, high therapeutic efficacy against cancer, and minimal adverse effects. Overall, this nanocomposite is a candidate for targeted cancer chemotherapy. DOX is the most extensively studied drug that is loaded into carriers. Studies have focused on the development of DOXloaded HA-CNTs as drug carriers to deliver DOX to various human tumor cells, such as lung epithelial cancer cell line A549 cells and HeLa cells. For instance, Datir and colleagues91 reported a facile method to synthesize a therapeutic agent that is DOX loaded in HA-conjugated multiwalled CNTs (HAMWNTs) via a π−π stacking interaction. The in vitro and in vivo results showed that the cytotoxicity and tumor growth inhibitory effect of DOX-loaded HA-MWCNTs were higher than those of an equivalent concentration of free DOX while reducing drug-associated cardiotoxicity. Thus, these properties render the synthesized HA-MWNTs as suitable carriers in targetable drug delivery. In addition, other versatile nanomaterials based on HA-CNTs have been highlighted for drug delivery of anticancer agents for cancer treatment.95,99 Overall, these HA-CNTs have been used as targetable drug delivery systems. Compared with traditional chemotherapy, CNTs have recently received tremendous interest in laser-triggered PDT and PTT because of their strong light absorbance, high photothermal conversion efficiency, and low tissue toxicity. The fundamental issues in PTT are focused on selective and effective phototherapy agents. For this reason, a PTT nanoplatform based on HA-CNTs was recently developed. For example, hematoporphyrin monomethyl ether was introduced onto HA-CNTs for synergistic PTT and PDT antitumor therapy.100 In this study, the HA-CNTs nanomaterial had high optical absorbance in the NIR that can be applied for photothermal therapy. The results confirmed that the therapeutic effects of HA-CNTs are significantly higher than

none none not given HA-QD conjugate (CdSe)

properties

Figure 7. Schematic of the preparation of SAL-SWNTs-CHI-HA: chitosan (CHI)-coated SWNTs loaded with salinomycin (SAL) functionalized with HA. Reprinted from ref 97; Copyright 2014, with permission from Elsevier.

excellent fluorescence stability, no significant cytotoxicity biocompatibility and enhanced cellular uptake none none 7.5 HA-coated QDs ((CdSe)CdZnS)

stimuli responsive drug system

Mw of HA (kDa)

Table 2. continued

workers97 have fabricated a drug delivery system based on chitosan (CHI)-coated single-walled CNTs (SWNTs) loaded with salinomycin (SAL) and functionalized with HA (SALSWNTs-CHI-HA) with enhanced cellular uptake and therapeutic efficiency to gastric cancer stem cells (CSCs) (Figure 7). The results showed that the targeted drug delivery system

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However, a major obstacle for the biomedical application of HA-CNTs described in this section is the polydispersity of CNTs, which limits the reproducibility of the results and often affords inconsistent data. Furthermore, there are many pharmacology and toxicology challenges of these nanomaterials in vivo. Thus, more research on HA-CNTs should be devoted to considering these important unresolved issues and challenges. Despite the fact that there are still many unresolved issues and challenges in HA-CNTs nanomedicine, the unique physiochemical properties and biological activity of HA-CNTs are attractive for various novel applications in various biomedical fields. 2.5. HA-Functionalized QDs (HA-QDs) and HAFunctionalized Carbon QDs (HA-CQDs). Fluorescent semiconductor nanocrystals (known as QDs) consist of hundreds to many thousands of atoms, which have been widely used in biosensing and bioimaging because of their unique optical and electronic properties.105,106 Compared with conventional organic fluorescent dyes, QDs present many advantages, such as broad absorption spectra, symmetric sizetunable emission, high quantum yield, and strong resistance to photobleaching; these properties render QDs with a broad application potential in the biomedical field.107 However, the major concern for QDs is their high toxicity resulting from the use of heavy metals in their production.108 Therefore, improvement in biocompatibility of QDs is an important challenge in their biomedical applications. The application of QDs for specific absorption under physiological conditions has not yet been reported. To address this issue, researchers have achieved rapid progress in surface functionalization of QDs, providing fundamental insights into reduction of systemic toxicity and enhancement of cellular targetability. Surface functionalization of QDs with various biocompatible and bioactive compounds, such as lipids, antibodies, peptides, and polysaccharides, promotes their biomedical applications.106,109 Proper surface functionalization is vital for successful application of QDs in biomedicine. Among the QDs, polysaccharide-functionalized QDs have gained increasing attention because of their unique physiochemical and biological properties. HA-QDs not only reduce the systemic side effects of QDs but also render cancer cells targetable. Studies have focused on fabricating HA-QDs and investigating their biomedical application as bioimaging agents.42,110,111 For example, Kim and colleagues112 have explored the use of QDs (CdSe) as bioimaging agents to assess the possibility of using HA derivatives as target-specific drug delivery carriers for the treatment of liver diseases. Expectedly, the HA-QDs demonstrated a promising ability to actively target cells that cause chronic liver diseases through endocytosis. The results showed that HA and its derivatives demonstrated biocompatibility and cellular uptake characteristics, suggesting their potential as promising drug carriers for the treatment of various chronic liver diseases. To explore the targetable and biocompatible imaging agents, Bhang and colleagues fabricated HA-QD nanocomposites through simple electrostatic attraction between HA and QDs (CdSe/CdS/ZnS core/shell/shell) for cancer imaging and realtime visualization of changes in lymphatic vessels (Figure 9).113 Their work validated that HA-QDs exert significantly low cytotoxicity. In addition, they can label and visualize the lymphatic vessels in vitro and in vivo, reflecting the feasibility of using HA-QD nanocomposites as a biocompatible and targetable bioimaging agent. Overall, these techniques have

those of PTT or PDT treatment. In a follow-up study, another nanoplatform, a nanophototherapy agent formed by conjugating ICG to HA nanoparticles encapsulated with SWCNTs, was tested for PTT and PDT treatments.94 The obtained nanoplatform exhibits favorable structural stability, biocompatibility, targetability, and photothermal conversion efficiency, indicating the potential application of this nanophototherapy in CD44-targeted and image-guided dual PDT and PTT (Figure 8). The excellent properties of the nanoplatform allow for new

Figure 8. Schematic of the formation of a dual targeted phototherapy agent, that is, ICG-conjugated to HA nanoparticles encapsulated with SWCNTs: CD44 targeted delivery of ICG-coupled HA nanoparticles into tumors followed by phototherapy using an NIR laser to irradiate the tumor area. Reprinted from ref 94; Copyright 2016, American Chemical Society.

exploration on the applications of PDT and PTT, and this nanoplatform demonstrates potential clinical translation. These nanocomposites are candidates for targeted PTT and PDT cancer treatment through sequential irradiation-activated apoptotic therapy. In addition to tumor-targeting drug delivery agents, HA-CNTs can enhance bone repair and regeneration and serve as a biosensing platform.101−103 As mentioned above, several studies in the biomedical field have reported that HA-functionalized CNTs demonstrate enhanced biocompatibility, physiological stability, and the absence of severe toxicity. However, the safety profile of CNTs remains largely undefined, limiting their practical application. To address this problem, researchers have conducted pioneering works to investigate the hazardous effects of MWCNTs. For example, exposure to MWCNT can lead to inflammation, fibrosis, and granuloma formation in lungs. Therefore, evaluating the health risks of MWCNTs is urgently needed. An important application of the HA-MWCNT nanocomposite in reducing pulmonary injury was not discovered until recently.104 The results demonstrated that HA in the nanocomposite significantly eliminated lung injury and reduced MWCNT-induced epithelial injury. In light of the concerns regarding HA-CNTs, we present in this section the progress made in the biomedical applications of HA-CNTs, which are summarized in Table 2. We highlight the important HA- and CNT-based nanocomposites reported in the literature, discuss their properties, and envision their applications. The problem of specificity of CNTs in cell targeting may be solved by using HA as a targeting ligand. 1686


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imaging. However, there are several limitations associated with using HA-QDs and HA-CQDs in the biomedical field because QDs are highly toxic at relatively low levels,119,120 even functionalized with HA, which may limit their use in clinical studies. The extent of cytotoxicity of HA-QDs and HA-CQDs in vivo needs to be determined. Another important issue is the lack of fundamental research concerning the effect of complex biological environments (salts, pH, and temperature) on optical properties of HA-QDs and HA-CQDs. In conclusion, irrespective of work on HA-QDs and HA-CQDs, further studies concerning these specific problems are still needed to meet specific requirements in clinical applications. 2.6. HA-Functionalized Mesoporous Silica Nanomaterials. Mesoporous silica nanoparticles (MSNs) have been attracting significant attention in various nanotechnological applications, such as adsorption, catalysis, sensing, and separation owing to their outstanding properties, such as controlled particle size, high surface area and pore volume, welldefined pore structures, and chemical stability.125,126 In addition, MSNs are excellent nanomaterials on the basis of their potential biomedical applications.127,128 In particular, researchers have investigated MSNs, which are advanced drug delivery nanocarriers that demonstrate improved drug loading and controlled delivery properties owing to their physiochemical properties described above, excellent biocompatibility, degradability under physiological conditions, and facile functionalized surface.129,130 However, several key factors limit the clinical application of MSNs. For example, a drug delivery system based on MSNs cannot transport drugs to specific target sites without any drug leaking into the blood circulation. Thus, the development of MSN nanocarriers that can transport and release drugs to specific sites in a selective and controlled manner has strongly attracted the attention of researchers. In overcoming this problem, MSNs functionalized with active targeted ligands, such as enzymes, antibodies, and polysaccharides, were designed and applied as controlled drug delivery carriers, and they simultaneously increase colloidal stability, biocompatibility, targetability, and precise drug release.128,131 HA-functionalized MSNs (HA-MSNs) have been developed as intelligent nanocarriers to achieve targeted and controlled drug delivery into special cancer cells.132 Recently, Zhao et al.133 have developed a redox and enzyme dual-stimuli responsive delivery system (MSN-SS-HA) based on HA-conjugated MSNs by cleavable disulfide (SS) bonds (Figure 10). The MSN-SS-HA nanomaterials had long-term stability and excellent dispersibility in physiological PBS as well as good biocompatibility. The strong tendencies of agglomeration and precipitation under physiological conditions have strongly limited the practical use of MSNs in biomedical fields.130 The potential biomedical applications of MSNs have resulting in significant effort toward addressing the problem of MSN dispersion. Recent works aiming to achieve this goal include the work of Ma and co-workers, who reported a novel synthesis method for HA-MSNs through a facile amidation reaction.134 The results showed that the HA-MSNs exhibited excellent colloidal dispersibility in physiological fluids. Furthermore, it can selectively target specific cancer cells overexpressing CD44 receptors. In HeLa cells, the therapeutic effect of CPT drug encapsulated into HA-MSNs was superior to those of both free CPT and CPT-loaded HA-MSNs in the presence of excess free HA. Therefore, HA-MSNs are a potential new carrier for siteselective, controlled-release delivery of anticancer drugs.

Figure 9. Schematic of an HA-QD conjugate with HA conjugation positively modifying QDs through multiple electrostatic adsorptions. Reprinted from ref 113; Copyright 2009, American Chemical Society.

validated the use of QDs in biomedical applications, resulting in reduced cytotoxicity and enhanced targetability for bioimaging and drug delivery. Although a considerable amount of effort has been put toward improve the biocompatibility of QDs, the inherent cytotoxicity of QDs is one of the major obstacles limiting their further clinical application. This issue prompted the fabrication of an alternative material, CQDs, which have attracted attention because of their inherently low toxicity, excellent biocompatibility, low cost, remarkable optical properties, and chemical inertness.114 They have been applied in various biomedical fields, including in bioimaging, biosensing, drug delivery, and cancer therapies. However, the lack of specific cell targeting on the surface of CQDs has been a critical problem to overcome in their biomedical applications. Therefore, for achieving increased cell selectivity, facile surface functionalization is required to generate CQDs with high fluorescence stability and superior biocompatibility and targetability. On the basis of these considerations, HA-CQDs have recently attracted increasing attention and were successfully designed and used for targeting specific bioimaging and tumor theranostics.115 An example was presented by Zhang and colleagues,116 who synthesized and utilized HA-CQDs as a real-time bioimaging agent for targeted specific delivery of HA derivatives, whereas fluorescent CQDs were used as a bioimaging agent for cancer cells. Given the high targeting ability of HA with CD44, the HA-CQDs expectedly showed a high target-specific delivery of HA-CQDs into the liver. The synthesized HA-CQDs possessed uniform size distribution, a highly hydrophilic surface, and superior fluorescence. The results confirmed that the HA-CQDs can not only be used as a drug delivery carrier to treat liver diseases but is also a promising bioimaging agent. In other works, HA was introduced on the surface of CQDs and graphene QDs (GQDs) to enhance their targetability.117,118 These findings have confirmed that CQDs and GQDs can be used as in vivo fluorescent probes and in vitro drug transporters. In addition to serving as drug carriers and fluorescent tracers, HA-CQDs have been designed for tumor diagnosis and chemotherapy. HA-QDs and HA-CQDs have been increasingly attracting attention for simultaneous drug delivery and fluorescent tracking primarily because of the integration of the optical properties of QDs or CQDs and the cancer cell targetability of HA. Table 2 shows HA-QDs and HA-CQDs for molecular 1687


4T1 cells MR imaging and targeted drug delivery small dimensions, sustained drug release, high superparamagnetism, enhanced colloidal stability and cellular uptake DOX 100

none

142 mesenchymal stem cells useful component of scaffolds for bone tissue regeneration approaches enhance the osteogenic differentiation of human mesenchymal stem cells none none

none Docetaxel 370

none CPT 18

HA-conjugated C and Si nanocrystal-MSNs 8-hydroxyquinolineloaded HA-MSNs HA/poly-L-lysine bilayered silica nanoparticles magnetic/HA silica nanotubes

pH/redox DOX 200

1200− 1800

141

136

MCF-7 and MDA-MB-468 cells MCF-7 cells eradication of breast cancer cells and stem cells

targeted drug delivery to CD44-overexpressing cancer cells

cancer theranostics

133

140

MCF-7 and MDA-MB-231 human breast cancer cells HCT-116 cells targeted drug delivery system to cancer stem-like cells DOX not given

HA-mesoporous carbon spheres oligosaccharide HAmesoporous silica HA-coated C60 fullerene-silica nanoparticle MSN-SS-HA

none

redox 6-mercaptopurine

high stability, biocompatibility, and cell uptake

redox

100;138 200139 not given

high drug loading and anticancer efficiency

ultrahigh loading and encapsulation efficiency, high antitumor efficacy long-term stability, excellent dispersibility, good biocompatibility high drug delivery efficiency, NIR-to-vis luminescence imaging high antitumor efficacy, little systemic toxicity

28 HCT-116 cells

138,139 HCT-116 cells/HeLa cells

134,137

ref tumor models

HeLa cells/colo-205 cancer cells

enhanced site-specific delivery of anticancer drug for different tumors, drug delivery system for colon cancer therapy targeted codelivery of drugs to tumors overexpressing CD44 receptors stimulus-responsive targeted drug delivery system

applications properties

excellent colloidal dispersibility, high therapeutic efficiency none

carboplatin, camptothecin, 5-fluorouracil DOX

stimuli responsive drug Mw of HA (kDa) carrier

Table 3. Various Drug Delivery Systems Derived from HA-MSNs 1688

18;134 35137

Several MSN-based controlled drug delivery systems have been synthesized by using HA capping agents that can deliver drugs without any loss before reaching the target location. As mentioned earlier, HA-functionalized MSN-based drug delivery systems display several unique features, such as high colloidal stability, biodegradability, biocompatibility, and site-specific delivery. In recent years, stimuli-responsive drug delivery systems based on HA-MSNs that release loaded drugs in response to photodynamic treatment, redox potential, and pH have also received widespread attention. As discussed above, MSNs have been utilized in drug delivery systems. Besides drug carriers, it has been proven that MSNs can also be used in bioimaging.135 In most studies, the source of the fluorescence encapsulated within MSNs is dye. Instead of dye, the Shi group designed a new type of theranostic nanoplatform based on HA-functionalized carbon and Si nanocrystals encapsulated in MSNs.136 Their results showed that such nanomaterials could specifically target cancer cells overexpressing CD44, exhibiting high drug delivery efficiency, and simultaneously image the cancer cells in the NIR-to-vis luminescence imaging fashion without using fluorescence dye. Table 3 summarizes the major drug delivery systems and bioimaging applications derived from HA-MSNs. Despite the exciting recent progress in cellular systems, several key challenges need to be overcome to further facilitate the development of HA-MSNs for biomedicine applications. First, protocols for the reproducible synthesis and functionalization of HA-MSNs are critical for this process. Additionally, efforts are still needed to study the long-term biocompatibility and pharmacokinetics of HA-MSNs. 2.7. HA-Functionalized Magnetic Nanoparticles (HAMNPs). Magnetic resonance imaging (MRI) has emerged as a powerful tool for sensitive and specific detection of early stage cancers because it is noninvasive and provides high-resolution and tomographic real-time images at the cellular and molecular levels.144 MNPs have been extensively utilized in many biomedical applications, such as MR imaging contrast agents and drug delivery vehicles for the detection and treatment of cancer and other diseases; MNPs are utilized primarily because of their chemical stability and ability to function in biological interactions at the cellular and molecular levels.145 However,

HA-SiO2 nanoparticles

Figure 10. Schematic structure of MSN-SS-HA and dual stimuliresponsive targeted drug delivery system, including (A) drug-loading process of MSN-SS-HA, (B) magnified image of the pore structure after the grafting of HA, (C) cell uptake through a CD44 receptormediated interaction, and (D) GSH-triggered drug release inside the tumor cell. Reprinted from ref 133; Copyright 2015, Acta Materialia Inc. with permission from Elsevier.

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Biomacromolecules one of the major challenges in MNPs is that hydrophobic ligands on the surfaces lead to colloidal instability in aqueous solutions. Therefore, the surface of MNPs must be modified to ensure their efficient dispersion in liquid media. Various natural and synthetic polymers, such as dextran and PEG, have been evaluated as coatings for MNPs.145 In another aspect, although MNPs can be nonspecifically taken up by cells, the development of specific amounts of targeting moieties on MNPs can facilitate the most efficient cellular uptake and imaging in vitro. Natural polymer HA, an attractive targeting ligand, has been widely used for functionalization of MNPs. Researchers have developed HA-MNPs and investigated their biological applications, and their results provide many approaches for targeted diagnosis and treatment of CD44-overexpressing cancers through receptor-mediated endocytosis.146 In recent years, HA has been one of the most widely utilized natural polymer coatings for MNP modification for in vivo applications.147,148 To successfully integrate HA onto the surface of MNPs (Fe3O4), researchers have explored many strategies, including physical interaction or covalent bonding.149 As therapeutic tools, HA-MNPs (MnFe2O4) have been extensively applied for targeted detection and diagnosis of CD44-overexpressing breast cancer through MR imaging.150 Lim and co-workers21 have developed HA-MNPs (MnFe2O4), which exhibited superior biocompatibility and excellent capability for targeted detection and diagnosis of CD44overexpressing breast cancer via MRI, suggesting that the nanocomposites present promising potential applications as MR imaging contrast agents for accurate tumor diagnosis and therapy (Figure 11).

Figure 12. Schematic illustration of the preparation of HA-coated Fe3O4 for tumor-targeted bimodal imaging and photodynamic/ hyperthermia treatment. (A) Acetylated HA-pheophorbide-a (AHP)coated Fe3O4 magnetic nanoparticles (AHP@MNPs) interacting with positively charged MNP through multibinding interactions. (B) AHP@MNPs irradiated with magnetic and near-infrared lasers for tumor-targeted bimodal imaging and photodynamic/hyperthermia treatment. Reproduced from ref 152 with permission of The Royal Society of Chemistry. http://dx.doi.org/10.1039/C6NR02273A.

dynamic/hyperthermia-combined treatment. Overall, several studies have reported on the fabrication of HA-MNPs for molecular imaging, particularly in combination therapy for cancer diagnosis and treatment.153−157 Some typical systems based on HA-MNPs as imaging contrast agents and as drug carriers for cancer treatment are summarized in Table 4. When selecting HA-MNPs for drug delivery and molecular imaging systems, many important issues should be considered including but not limited to their pharmacokinetics, cytotoxicity, and stability as well as their biodegradability, biocompatibility, and potential side effects. Additionally, one important goal for further designing HA-MNPs is to improve the bloodbrain barrier (BBB) transport of MNPs. As far as the preparation technology of nanoparticles is concerned, it should be noted that the layer-by-layer (LbL) technology that utilizes the process of sequentially depositing oppositely charged polymers to build highly stable films on substrates has been a new and highly promising approach for nanomedicine applications.160 In addition to the HA-functionalized nanohybrid materials described above, great progress in HA employed for the preparation of LbL nanoparticles has been achieved for biotechnological and biomedical applications. For example, recent studies have demonstrated the use of HALbL nanoparticles (such as PS latex nanospheres, AuNPs, and QDs) for tumor-specific cancer diagnostics, therapy, and systemic delivery.161,162 Highly versatile HA-LbL nanoparticles as tailor-made delivery vehicles have been shown to be capable of enhancing the efficacy and specificity of therapeutics. Taking advantage of the LbL-assembled multilayered nanoparticles with various sizes, architectures, and chemical compositions, an available powerful platform can be constructed for drug encapsulation, triggered drug release, and hierarchical assemblies.

Figure 11. Schematic illustration of HA-MNCs (MnFe2O4) for diagnosis of CD44-overexpressing breast cancers by magnetic resonance imaging (MRI). Reprinted from ref 21; Copyright 2011, with permission from Elsevier.

Another paradigm for cellular imaging using HA-MNPs was introduced by Chung and co-workers.151 In this work, HAfunctionalized iron oxide nanoparticles could efficiently label human mesenchymal stem cells with low toxicity and could greatly enhance MRI contrast, demonstrating their promising potential application as imaging probes in the biomedical field. Additionally, multifunctional magnetite nanoparticles composed of Fe3O4 nanoparticles and photosensitizer-conjugated HA were prepared to achieve enhanced tumor diagnosis and therapy (Figure 12).152 The results suggested that the multifunctional magnetite nanoparticles could target tumors with enhanced tumor therapeutic effects through photo-

3. LIMITATIONS OF HA THAT MAY IMPACT HA-BASED NANOHYBRID MATERIALS A multitude of reports demonstrate that HA can modulate many biological effects such as cell adhesion and migration, tumorigenesis, cell survival and apoptosis, inflammation, and so 1689


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Table 4. Typical Systems Based on HA-MNPs as Imaging Contrast Agents and as Drug Carriers for Cancer Treatment Mw of HA (kDa)

imaging mode

properties

applications

ref

HA-coated MNPs (Fe3O4) HA-modified Fe3O4

31 5.8

MRI MRI

high colloidal stability, excellent cell labeling efficiency negative contrast agent

158 159

HA-functionalized iron oxide nanoparticles (IONPs)/PEG HA-modified MnFe2O4

17

MRI

low toxicity and enhanced MRI contrast

20

MRI

effective CD44 binding ability, high cell viability

cell labeling and in vivo imaging detecting endometriosis in a mouse model specifically label mesenchymal stem cells accurate breast cancer cell diagnosis drug delivery vehicles and theranostic platform

tumor-targeted bimodal imaging and photodynamic high biocompatibility, controllable particle sizes, hyperthermia combination desirable magnetic properties, tumor growth inhibition therapy efficacy excellent biocompatibility and superior targeting detect CD44-overexpressing efficiency with MR sensitivity breast cancer no cytotoxicity, colloidal stability, targeted imaging diagnose tumor regions and efficacy detect CD44 abundant cancer cells

148

system

HA-coated superparamagnetic iron oxide nanoparticles (HASPIONs) HA-conjugated SPIONs

not given

MRI

enhance the efficacy of chemotherapeutic drugs, noninvasive monitoring delivery

6.8

MRI

nontoxic, biocompatible, effective cancer targeting

AHP-coated MNPs (Fe3O4)

5.8

MRI

HA-modified MnFe2O4

1000

MRI

HA-modified MnFe2O4

20

MRI

forth.163 In addition, many researchers have established the concept that HA plays different roles depending on its molecular weight. For example, high molecular weight HA (generally over 1000 kDa) has been shown to be antiinflammatory; however, low molecular weight HA promotes the production of inflammatory mediators and induces tumor progression.164−166 Therefore, the molecular weight variants of HA used in a variety of biomedical applications have elicited varying biological responses.167 It is not rare to see such a fact in polysaccharides. Another important issue is the degradation of HA. HA is readily degraded into smaller fragments in the human body by enzymatic degradation of hyaluronidase (HAse), which specifically hydrolyzes the β-1,4 linkage of the HA molecules.168 It should be noted that the molecular weight of HA may affect the HA uptake by cells and modulate biological responses, although the exact mechanism is still far from completely understood.169 It has been shown that low molecular weight HA derived from high molecular weight HA has distinct biological functions.170 These limitations or defects of HA itself like easy degradability and negative effects arising from low molar mass HA are often neglected in fabricating nanohybrid materials in most of the published literature. Furthermore, as described earlier, HA and its conjugates have been extensively utilized in biomedical applications mostly due to its high binding affinity to the CD44 receptor. Therefore, maintaining the unique biological property of HA binding to the CD44 receptor is very important when modifying HA. It has been reported that CD44 interacts with a minimum HA length of 6−8 saccharides,171 i.e., only a small targeting moiety (oligosaccharide) interacts with the CD44 receptor, which facilitates the utilization of HA conjugates in drug delivery. In many of the studies described above (e.g., refs 94, 97, and 123), the intracellular uptake of HA derivatives by CD44-mediated endocytosis has been confirmed by using fluorescently labeled HA derivatives. These results show that HA derivatives can be specifically and efficiently internalized into CD44-overexpressed cells. However, notably, there has been clear evidence that excessive chemical modification of HA will alter its biological functions. For example, although 35 mol % HA modification maintained the ability to bind CD44, 68 mol %

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modification lost this unique biological function of HA.110 To our knowledge, there are few studies that have investigated the effect of chemical modification of HA on the HA−CD44 interaction. Therefore, taking into account the importance of maintaining the unique biological functions of HA, attention must be paid to ensure the CD44 binding ability of HA-based nanomaterials. Therefore, despite many excellent properties of HA, several limitations of HA associated with using it to functionalize nanomaterials for biomedical applications should be stressed, which include (1) the fact that, despite chemical modification of HA controlling the degradation rate, how to exactly control and reduce the degradation rate of HA into fragments in the human body remains a challenge; (2) at what level the degree of chemical modification of HA can retain the binding ability of HA to the CD44 receptor; (3) the fact that low molecular weight HA may accumulate in the body, leading to local deposits that may cause unwanted side effects in the long term; and (4) the fact that low molecular weight HA that may induce the expression of proinflammatory cytokines, chemokines, and growth factors, which may cause adverse effects on the body and severely limit the extensive applications of HA-functionalized nanomaterials in the biomedical field. Hence, more extensive studies are still needed to fully clarify the influence of HA-functionalized nanomaterials on biological effects, which will enable us to bring more innovative applications of HAfunctionalized nanomaterials without progression to inflammatory disease.

4. CONCLUSIONS AND FUTURE PERSPECTIVES The application of nanotechnology in the biomedical field is widely expected to change the landscape of pharmaceutical and biotechnology industries for the foreseeable future. Over the past several decades, various nanomaterials, especially Au, Ag, carbon materials, mesoporous materials, and MNPs have been developed for biomedical applications as imaging probes, drug carriers, and contrast agents owing to their unique structures and several distinctive physical and chemical attributes. Although significant progress has been made in the field of nanomaterials, several significant challenges must be investigated and addressed to promote the practical applications of 1690


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questions will undoubtedly accelerate the development of HA-nanomaterials for biological applications. In closing, rapid advances in the development and applications of HAnanomaterials in many biomedical fields underlie the great potential and important role of HA in these nanomaterials. As research in HA-nanomaterials progresses, we look forward to developing more innovative strategies for broadening their biomedical applications.

these nanomaterials. For example, the most important disadvantage of these nanomaterials is potential toxicity related to long-term safety, which has greatly limited their clinical translation. In addition, these nanomaterials cannot be specifically taken up by target cells, and they lack stability under physiological conditions. Therefore, to overcome these limitations, researchers have focused on the functionalization of nanomaterials while retaining their inherent unique physiochemical properties. Since its discovery, HA has been widely used and has gained success in the cosmetic and biomedical fields. HA can be employed as a carrier and targeting ligand for the selective accumulation of therapeutic and diagnostic entities in diseased areas overexpressing CD44 receptors. In this review, we have summarized the recent developments in HA-nanomaterials, including AuNPs, AgNPs, graphene derivatives, CNTs, QDs, CQDs, and mesoporous materials to MNPs. Moreover, this review highlights the applications of HA-nanomaterials in the biomedical field, such as in drug delivery, bioimaging, and detection and diagnosis of cancer cells. These applications have attracted the interest of many researchers globally. Numerous studies on HA-nanomaterials are in progress, and many interesting applications of HA-nanomaterials have been demonstrated by diverse research groups; the biomedical applications of these nanomaterials range from tissue engineering and molecular imaging to targeted drug delivery. Various applications of HA-nanomaterials are expected to be further investigated, although scale-up production of HA-nanomaterials may remain a major challenge. For the further development of HA-nanomaterials for biomedical applications, the following studies, including some important considerations, should be emphasized: (1) even though it has been reported that HA-nanomaterials are nontoxic in vitro, it is important to investigate the long-term toxicity of exposure to these nanomaterials on human physiology; (2) equally important is considering how the HA-nanomaterials size, shape, structure, conjugated ligands, surface properties, and polydispersity influence the pharmacokinetics, biodistribution, and eventual side effects in vivo (these deep investigations can provide reproducibility of the results to obtain consistent data); (3) when we design the HAnanomaterials utilized in drug delivery and bioimaging systems, more research should be performed considering the balance between the biological activities of HA and the physiochemical properties of inorganic nanomaterials; (4) HA-nanomaterials should be an effective platform for the delivery of anticancer drugs to overcome biological barriers (e.g., vascular or cellular barrier, blood−brain barrier); (5) more investigations are still needed to obtain a better understanding of how we can extrapolate the potential effects on human health from their biological behaviors observed in animal studies; (6) further work should aim at designing and preparing HA-nanomaterials that can be used in large-scale applications in the biomedical field; (7) with knowledge gained concerning how the molecular weight of HA influences biological effects, new developments of HA-functionalized nanomaterials and relevant strategies are needed to make either HA itself or modified nanomaterials more biocompatible and worthy of approval; and (8) HA has positive interactions with proteins, nucleic acids, and other biological compounds, which will lead to research into the introduction of proteins and nucleic acids in HA-nanomaterials. These ideas would broadly expand the prospects for HAnanomaterials in the biomedical arena. Addressing these

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Hongbin Zhang: 0000-0002-4419-4818 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors are thankful for the financial support for this work from the National Natural Science Foundation of China (Grants 21074071 and 21274090).

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ABBREVIATIONS HA, hyaluronan; HAase, hyaluronidase; Mw, molecular weight; AuNPs, gold nanoparticles; AgNPs, silver nanoparticles; GO, graphene oxide; rGO, reduced graphene oxide; CNTs, carbon nanotubes; CHI, chitosan; CSCs, gastric cancer stem cells; QDs, quantum dots; Cdots, carbon dots; GQD, graphene quantum dot; MSNs, mesoporous silica nanoparticles; DOX, doxorubicin hydrochloride; CPT, camptothecin; CPT-11, irinotecan hydrochloride; TPT, topotecan hydrochloride; βCD, β-cyclodextrin; CHA, cholesteryl-modified HA; BPEI, branched polyethylenimine; SAL, salinomycin; HCV, hepatitis C virus; IFNα, interferon α; ROS, reactive oxygen species; PS, polystyrene; NIR, near-infrared; SPR, surface plasmon resonance; EPR, enhanced permeation and retention; ADH, adipic acid dihydrazide; BSA, bovine serum albumin; SERS, surface-enhanced Raman scattering; SP, spiropyran; CT, X-ray computed tomography; SPECT, single-photon emission computed tomography; MRI, magnetic resonance imaging; FTIC, Fluorescein isothiocyanate; Py, Pyrene; Vis, visible light; CDDSs, controlled drug delivery systems; PTT, photothermal treatment; ICG, indocyanine green; PDT, photodynamic therapy; EDC, N-ethyl-N′-dimethylaminopropyl-carbodiimide; NHS, N-hydroxysuccinimide; SWNTs, single-walled CNTs; MWNTs, multiwalled CNTs; MDR, multidrug resistance; MNPs, magnetic nanoparticles; SPIONs, superparamagnetic iron oxide nanoparticles; AHP, acetylated HA-pheophorbide-a; LbL, layer-by-layer; BBB, blood-brain barrier

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REFERENCES

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