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Cancer nanomedicine: mechanisms, obstacles and strategies Huafei Li*, ‡ ,1,2,3,6 , Hai Jin‡ ,4 , Wei Wan‡ ,5 , Cong Wu4 & Lixin Wei2 1
Department of Pathology, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, PR China Tumor Immunology & Gene Therapy Center, Third Affiliated Hospital of the Second Military Medical University, 225 Changhai Road, Shanghai, 200438, PR China 3 International Joint Cancer Institute, Translational Medicine Institute, the Second Military Medical University, 800 Xiangyin Road, Shanghai, 200433, PR China 4 Department of Thoracic Surgery/LaboratoryDiagnosis, First Affiliated Hospital of the Second Military Medical University,168 Changhai Road, Shanghai, 200438, PR China 5 Department of Orthopedic Oncology, Spine Tumor Center, Second Affiliated Hospital of the Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, PR China 6 School of Life Sciences, Shanghai University, 333 Nanchen Road, Shanghai, 200444, PR China *Author for correspondence: huafey
[email protected] ‡ Authors contributed equally 2
Targeting nanoparticles to cancers for improved therapeutic efficacy and decreased side effects remains a popular concept in the past decades. Although the enhanced permeability and retention effect serves as a key rationale for all the currently commercialized nanoformulations, it does not enable uniform delivery of nanoparticles to all tumorous regions in all patients with sufficient quantities. Also, the increase in overall survival is often modest. Many factors may influence the delivering process of nanoparticles, which must be taken into consideration for the promise of nanomedicine in patients to be realized. Herein, we review the mechanisms and influencing factors during the delivery of cancer therapeutics and summarize current strategies that have been developed for the fabrication of smart drug delivery systems. First draft submitted: 8 January 2018; Accepted for publication: 18 April 2018; Published online: 23 July 2018
The main therapeutics of cancer are surgery, radiotherapy and chemotherapy as well as the new concept of cancer biotherapy (including cancer immunotherapy), which has been well documented since the 19th century when William B Coley observed that the injection of bacterial products in and around tumors can eliminate tumor cells [1,2]. Although surgical resection, which is primarily employed to remove the tumor mass, plays a pivotal role in the treatment of cancers, most patients are already in locally advanced or metastatic disease at the time of diagnosis, lacking the opportunity for radical surgery [3,4]. Radiotherapy, which eliminates cancer cells by DNA damaging, is also mainly applied in treating a tumor confined to a discrete anatomical area [5]. As a systemic therapy, anticancer drugs, either employed in chemotherapy or biotherapy, are able to treat cancer throughout the body, especially for patients with metastases [6]. However, their therapeutic efficacy is often modest to negligible owing to the low specificity and stability [7,8]. In order to obtain optimal therapeutic effects, the right drugs should be delivered to the right location of the right patient at the right time with the right concentration [9]. However, this ideal concept can hardly be achieved on account of the disparate transient states of drugs in adhesion, distribution, metabolism and excretion [7,9]. In the past decades, nanoparticle (NP)-based drug delivery systems (DDSs) provide new hopes for improving the efficiency of anticancer agents [10]. Nanomedicine is advantageous over conventional medicine for cancer therapy first because NPs (with desired size of tens to hundreds of nanometers) can be passively accumulated in cancers via the enhanced permeability and retention (EPR) effect due to malformed vascular walls with leaky cell-to-cell junctions and dysfunctional lymphatics in tumorous tissues [11]. Second, NPs decorated with various targeting ligands can actively bind to specific targets on tumor cells or in tumor microenvironment (TME), further enhancing their accumulation [12]. Third, many tumor types are resistant to multiple cytotoxic drugs, which occurs as an inherent defense mechanism and/or as a de novo acquired resistance mechanism following repeated exposure to anticancer therapeutics. The elevated expression of various drug efflux pumps, which are ascribed to ATP-binding cassette
C 2018 Future Medicine Ltd 10.2217/nnm-2018-0007
Nanomedicine (Lond.) (2018) 13(13), 1639–1656
ISSN 1743-5889 1639
Review
Li, Jin, Wan, Wu & Wei
(ABC) superfamily expressed on cytomembranes, are validated to be involved in the drug resistance; while the NPs, which are not physically recognized as substrates by the ABC efflux pumps, have the potential to overcome these problems [13]. Besides, NPs can be further equipped for codelivery of two or more bioactive agents [14], release payloads via a trigger at desired space and time, such as temperature [15], pH [16] or enzymatic catalysis [17]. The encapsulation of bioactive molecules has allowed for their protection from degradation, increasing their solubility in biological fluids [18,19]. Until now, many studies have shown better utility of NPs for detecting and killing cancer cells in in and ex vivo studies, however, the clinical translation of NPs has been limited [14]. Although less toxic than conventional therapies, US FDA approved nanotherapeutic agents are still associated with adverse effects, such as stomatitis and R R and Caelyx ) [20], and sensory neuropathy palmar–plantar erythrodysesthesia for liposomal doxorubicin (Doxil R and nausea for albumin-bound paclitaxel (Abraxane ) [21]. Also, the increase in overall survival is modest for many cases [14]. Here, we review the major factors influencing the efficacy and uniform delivery of NPs and summarize the advanced strategies that have been developed to overcome these obstacles.
Mechanisms & influences concerning drug delivery from circulation to cancer cells
In vivo NP delivery process Anticancer drug delivery from systemic circulation to cancer cells is a four-step process: transport through blood circulation to tumor regions via blood vessels; transport across vasculature walls into surrounding tumor tissues; penetrate through the interstitial space to target cells; and cellular uptake by endocytosis and intracellular delivery [7,22,23]. Current studies demonstrate that five main different mechanisms participate in the endocytosis of NPs by target cells, including phagocytosis, clathrin-mediated endocytosis, caveolin-mediated endocytosis, clathrin/caveolae-independent endocytosis and micropinocytosis [23]. Physiochemical characteristics of NPs influencing the delivery The biological performance (including biodistribution, pharmacokinetics, cellular uptake, therapeutic efficacy and side effects) of NPs is controlled by a series of complex and interrelated physicochemical characteristics including size, geometrical shape and surface properties via positively or negatively affecting the above-mentioned steps [22]. Owing to larger pores in tumorous blood vessel walls, the vascular permeability and hydraulic conductivity significantly increased in cancers when compared with that in normal tissues, being the basis for the EPR effect [22,24]. The mechanistic data regarding EPR effect primarily come from xenografted animal models. Currently, Andrew JC et al.’s study revealed that therapeutic NPs (CRLX101) can accumulate within gastric tumors in humans but not adjacent, non-neoplastic tissue, directly establishing the viability and effectiveness of EPR effect in the clinic [25]. For optimal efficacy, therapeutic agents must reach tumors in amounts sufficient to kill cancer cells but at the same time should not have adverse effects in normal tissues. However, on one side, although larger therapeutic agents extravasate in tumor tissues from large vascular pores with greater specificity, the transport efficacy across tumor vascular wall and diffusion efficiency within tumors decreases with the increase in the size of the transported particles [26]. On the other side, although smaller molecules with a diameter of less than 10 nm (e.g., free chemotherapeutic drugs) can penetrate across the vascular wall with greater efficacy, they generally extravasate in most normal tissues causing undesired off-target effects [14]. Thus, increasing the particle size will provide selectivity at the cost of limited accessibility to and within disseminated tumors when dosed into the circulatory system, and vice versa [7,22,27]. Besides, when intravenously injected, NPs smaller than 5–6 nm cannot be intercepted by glomerulus, resulting in rapid clearance through urine with a plasma half-life of
