Colloids and Surfaces B: Biointerfaces Biodegradable ...

Colloids and Surfaces B: Biointerfaces 75 (2010) 1–18

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Colloids and Surfaces B: Biointerfaces journal homepage: www.elsevier.com/locate/colsurfb

Review

Biodegradable polymeric nanoparticles based drug delivery systems Avnesh Kumari, Sudesh Kumar Yadav, Subhash C. Yadav ∗ Biotechnology Division, Institute of Himalayan Bioresource Technology, CSIR, Palampur, HP 176061, India

a r t i c l e

i n f o

Article history: Received 18 June 2009 Received in revised form 28 August 2009 Accepted 2 September 2009 Available online 8 September 2009 Keywords: Biodegradable Polymeric nanoparticles Encapsulation efficiency Polylactic acid Polylactic acid co-glycolic acid Poly-␧-caprolactone Chitosan

a b s t r a c t Biodegradable nanoparticles have been used frequently as drug delivery vehicles due to its grand bioavailability, better encapsulation, control release and less toxic properties. Various nanoparticulate systems, general synthesis and encapsulation process, control release and improvement of therapeutic value of nanoencapsulated drugs are covered in this review. We have highlighted the impact of nanoencapsulation of various disease related drugs on biodegradable nanoparticles such as PLGA, PLA, chitosan, gelatin, polycaprolactone and poly-alkyl-cyanoacrylates. © 2009 Elsevier B.V. All rights reserved.

Contents 1. 2. 3.

4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Synthesis and encapsulation of drugs in polymeric nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poly-d,l-lactide-co-glycolide (PLGA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Encapsulation of various anticancer drugs on PLGA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.1. 9-Nitrocamptothecin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.2. Paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.3. Cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.4. Xanthones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.5. Rose bengal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.6. Triptorelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1.7. Dexamethasone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Encapsulation of diabetes drugs (insulin) on PLGA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3. Encapsulation of psychotic drugs (haloperidol) on PLGA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4. Encapsulation of hormones (estradiol) on PLGA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5. Encapsulation of tetanus drugs on PLGA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Polylactic acid (PLA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Encapsulation of psychotic drugs (savoxepine) on PLA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Encapsulation of restenosis drugs (tyrphostins) on PLA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Encapsulation of hormones (progesterone) on PLA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4. Encapsulation of oridonin on PLA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5. Encapsulation of protein (BSA) on PLA nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Poly-␧-caprolactone (PCL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1. Encapsulation of anticancer drugs on PCL nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1. Tamoxifen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.2. Taxol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author. Tel.: +91 1894233339x397; fax: +91 1894230433. E-mail address: [email protected] (S.C. Yadav). 0927-7765/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfb.2009.09.001

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5.2. Encapsulation of diabetes drugs (insulin) on PCL nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3. Encapsulation of clonezepam drugs on PCL nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4. Encapsulation of antifungal (amphotericin B) drugs on PCL nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Chitosan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.1. Encapsulation of antihormonal (glycyrrhizin) drugs on chitosan nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.2. Encapsulation of insulin on chitosan nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6.3. Encapsulation of ocular (cyclosporin A) drugs on chitosan nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Gelatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.1. Encapsulation of BSA on gelatin nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.2. Encapsulation of anticancer drug (paclitaxel) on gelatin nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.3. Encapsulation of oligonucleotides on gelatin nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Encapsulation of anti-HIV drug (didanosine) on gelatin nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Encapsulation of antimalarial drug (chloroquine phosphate) onto gelatin nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8. Poly-alkyl-cyano-acrylates (PAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.1. Encapsulation of antibacterial (ampicillin) on poly-alkyl-cyanoacrylates nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2. Encapsulation of anti-inflammatory (indomethacin) drugs on poly-alkyl-cyanoacrylate nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3. Encapsulation of various anticancer drugs on poly-alkyl-cyanoacrylate nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9. Modification of surface properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10. Drug loading and release mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Nanotechnology is now frequently used for various applications in fiber and textiles [1], agriculture [2,3], electronics [4], forensic science [5], space [6] and medical therapeutics [7–11]. However, biodegradable nanoparticles are frequently used to improve the therapeutic value of various water soluble/insoluble medicinal drugs and bioactive molecules by improving bioavailability, solubility and retention time [12]. These nanoparticle–drug formulation reduces the patient expenses, and risks of toxicity [13]. Nanoencapsulation of medicinal drugs (nanomedicines) increases drug efficacy, specificity, tolerability and therapeutic index of corresponding drugs [14–19]. These nanomedicines have many advantages in the protection of premature degradation and interaction with the biological environment, enhancement of absorption into a selected tissue, bioavailability, retention time and improvement of intracellular penetration [20]. Several disease related drugs/bioactive molecules are successfully encapsulated to improve bioavailability, bioactivity and control delivery [21–23]. Nanomedicines of the dreadful diseases like cancer [24], AIDS [25], diabetes [26], malaria [27], prion disease [28] and tuberculosis [29] are in different trial phase for the testing and some of them are commercialized [30,31]. Nanomedicine formulation depends on the choice of suitable polymeric system having maximum encapsulation (higher encapsulation efficiency), improvement of bioavailability and retention time. The desired nanomedicines are generally achieved by hit and trial method (no specific rule) however, the encapsulation process with polymeric nanoparticles are in more advance condition in comparison to other nanoparticle systems [32]. These drug nanoformulations (nanodrug) are superior to traditional medicine with respect to control release, targeted delivery and therapeutic impact. These targeting capabilities of nanomedicines are influenced by particle size, surface charge, surface modification, and hydrophobicity. Among these, the size and size distributions of nanoparticles are important to determine their interaction with the cell membrane and their penetration across the physiological drug barriers. The size of nanoparticles for crossing different biological barriers is dependent on the tissue, target site and circulation [33]. For the cellular internalization of the nanoparticles, surface charge is important in determining whether the nanoparticles would cluster in blood flow or would adhere to, or interact with oppositely charged cells

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membrane [34]. Cationic surface charge is desirable as it promotes interaction of the nanoparticles with the cells and hence increases the rate and extent of internalization [12]. For targeted delivery, persistence of nanoparticles is required in systemic circulation of the body. But conventional nanoparticles with hydrophobic surface are rapidly opsonized and massively cleared by the fixed macrophages of the mononuclear phagocytic system (MPS) organs. For increasing circulation time and persistence in the blood, surface of conventional nanoparticles are modified with different molecules. Coating of hydrophilic polymers can create a cloud of chains at the particle surface which will repel plasma proteins [35]. Finally, the performance of nanoparticles in vivo is influenced by morphological characteristics, surface chemistry, and molecular weight. Surface modified nanoparticles have anti-adhesive properties by virtue of the extended configuration on the particle surface which acts as steric barrier reducing the extent of clearance by circulating macrophages of the liver and promoting the possibility of undergoing enhanced permeation process [12]. Release mechanism can be modulated by the molecular weight of the polymer used. Higher the molecular weight of polymer slower will be the in vitro release of drugs [36]. Careful design of these delivery systems with respect to target and route of administration may solve some of the problems faced by new classes of active molecules. The synthesis process of biodegradable nanoparticles has been reviewed earlier [37]. Lowman group has published a review on the synthesis, surface modification, targeted delivery and release characteristic of biodegradable nanoparticles [38]. The synthesis and nanomedicine formulation of chitosan [39], PLGA [40], PLA [41] are well reviewed. However, the encapsulation of various diseases related drugs with various biodegradable nanoparticles and their applications are not reviewed yet. We have reviewed the encapsulation effects of different drug on various polymeric biodegradable nanoparticles, and its impact upon surface modification, bioavailability and drug release mechanisms. This paper reviewed the formulation of nanomedicine of known drugs of cancer, diabetes, malaria, etc., on the PLA, PLGA, PCL, chitosan, gelatin and poly-alkyl-acyanoacrylate nanoparticles. This review does not have the details of the synthesis and encapsulation of drug molecules. However, it provides the basic approach and nanotechnology applications in the therapeutic medicines of various diseases.


Fig. 1. Type of biodegradable nanoparticles: According to the structural organization biodegradable nanoparticles are classified as nanocapsule, and nanosphere. The drug molecules are either entrapped inside or adsorbed on the surface. (Originally adapted from [39] but modified.)

2. Synthesis and encapsulation of drugs in polymeric nanoparticles Polymeric nanoparticles have been synthesized using various methods [42] according to needs of its application and type of drugs to be encapsulated. These nanoparticles are extensively used for the nanoencapsulation of various useful bioactive molecules and medicinal drugs to develop nanomedicine. Biodegradable polymeric nanoparticles are highly preferred because they show promise in drug delivery system. Such nanoparticles provide controlled/sustained release property, subcellular size and biocompatibility with tissue and cells [43]. Apart from this, these nanomedicines are stable in blood, non-toxic, nonthrombogenic, nonimmunogenic, noninflammatory, do not activate neutrophils, biodegradable, avoid reticuloendothelial system and applicable to various molecules such as drugs, proteins, peptides, or nucleic acids [11]. The general synthesis and encapsulation of biodegradable nanomedicines are represented in Fig. 1. The drug molecules either bound to surface as nanosphere or encapsulated inside as nanocapsules.

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For the past two decades, countless work has been conducted to develop most effective nanomedicines from biocompatible and biodegradable nanopolymers [44]. The role of nanosystems for drug delivery through oral, nasal, ocular administration is reviewed by Alonso [45]. Pinto Reis et al. [42] reviewed the various methods of synthesis and encapsulation of different bioactive molecules on nanoparticles. Most of the reported methods are frequently used for the synthesis of biodegradable nanomedicines. Some of the commonly used methods are concisely described in this review along with each section and their encapsulation. The administration, activity and therapeutic importance of some medicinal drugs on different nanosystems are different, for example taxol (anticancer drug) nanomedicine have 100% and 20% encapsulation efficiency on PLGA [24] and PCL [30] nanodevices respectively. However, the therapeutic activity and stability of PCL nanomedicines are reasonably high than PLGA nanomedicine [30]. This part of review gave a brief analysis and sound information about current research in nanobiotechnology and their impact on therapeutics, development of novel nanomedicines, preparation process and their surface modification for the improvement of therapeutics (Table 1A). The most commonly and extensively used polymeric nanoparticles (poly-d,l-lactide-co-glycolide, polylactic acid, poly-␧-caprolactone, poly-alkyl-cyanoacrylates, chitosan and gelatin), their therapeutic advantages, general synthesis and encapsulation of various disease related drug have been described in this part of the review. 3. Poly-d,l-lactide-co-glycolide (PLGA) PLGA (poly-d,l-lactide-co-glycolide) is one of the most successfully used biodegradable nanosystem for the development of nanomedicines because it undergoes hydrolysis in the body to produce the biodegradable metabolite monomers, lactic acid and glycolic acid (Fig. 2). Since the body effectively deals with these two monomers, there is very minimal systemic toxicity associated by using PLGA for drug delivery or biomaterial applications. PLGA nanoparticles have been mostly prepared by emulsification–diffusion [46], solvent emulsion–evaporation [36], interfacial deposition [42] and nanoprecipitation method [47] (Fig. 3). Generally in emulsification–diffusion method, the PLGA polymers are dissolved in organic solvent (EtAc, MEK, PC, BA, etc.), poured and separated in aqueous phase having stabilizer and subsequently emulsified by homogenizer. In solvent evaporation method, the polymers are dissolved in volatile organic solvent (DCM, acetone, CHCl3 , EtAc, etc.) and poured into continuously stirring aqueous phase with or without emulsifier/stabilizer and sonicated. Interfacial deposition methods have been used for the formation of both nanocapsule and nanospheres. The nanoparticles are synthesized in the interfacial layer of water and organic solvent (water miscible) and finally the nanoparticles are

Fig. 2. Hydrolysis of PLGA nanoparticles: PLGA nanoparticles are biologically hydrolyzed in acidic medium into lactic and glycolic acid. These hydrolysis products have been metabolized in TCA cycle.

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Table 1A PLGA biodegradable polymeric nanoparticles for drug delivery. Polymer

PLGA

Structure of polymer

Release mechanism

Surface mod.

In vivo

References

100% Solvent evaporation/ solvent extraction technique

Slow release of the drug up to 20 days

Diffusion, matrix swelling and polymer erosion

TPGS

–

[24]

Paclitaxel

>90% Interfacial deposition method

Dissolution and diffusion

30% reduction in cell viability against NCI-H69 cells on incubating for 24 h.

[63]

Taxol

70%

48–75%Emulsion diffusion

More cytotoxic on Hela cells than taxol Smaller particles produced prolonged blood levels

[118]

Estradiol

Improved antitumoral efficacy as compared to free drug Greater tumor growth inhibition Enhanced bioavailability

9-Nitrocamptothecin

33%

Nanoprecipitation

Xanthones

77%

Solvent displacement technique

Docetaxel

87.3% Emulsion solvent diffusion

2-Aminochromone

93%

EE

Taxol

Thymopentin

Dexamethasone

SR-2508 (Etanidazole)

Synthesis methods

Nanoprecipitation

Solvent evaporation 31.03%Double emulsion solvent evaporation method 6% Solvent evaporation method 20.06%Emulsification solvent evaporative method

Controlled release up to 160 h Slow drug release up to 4 h

Superior cellular uptake over non-modified particles Slow drug release up to 2 weeks Enhanced intestinal bioadhesion

Diffusion

PEG

Diffusion and degradation of the polymeric matrix Diffusion Partition between the oil core and the external aqueous medium Diffusion and matrix erosion

Diffusion

[61] [67]

PEG

Greater extent of intracellular uptake in folate receptor cancer cells

[119]

DMAB

Improved arterial U-86 levels Highest amount of nanoparticles in small intestine

[120]

Lectins

Slow drug release up to 50 h

Diffusion

Drug retained its bioactivity and effectively sensitized two hypoxic tumor cell lines to radiation

Burst effect

[46]

DPPC

[121]

[22]

Radiosensitisation of SR-2508 loaded particles was more significant than the free SR-2508. Colony counts of hypoxic tumor cells was significantly lowered.

[122]


Therapeutic improvement

Encapsulant


5

Fig. 3. Different method for the synthesis of PLGA nanoparticles: Mostly, PLGA nanoparticles were synthesized by emulsion diffusion, solvent evaporation and nanoprecipitation methods.

separated by centrifugations [42]. Most commonly used method for the preparation of PLGA nanoparticles is nanoprecipitation. Acetone dissolved polymer are added drop-wise into continuously stirring aqueous phase with or without emulsifier/stabilizer and consequently organic phase is evaporated under reduced pressure (Fig. 3). PLGA nanoparticles have been used to develop the proteins and peptides nanomedicine, nano-vaccines, nanoparticles based gene delivery system, nano-antigen and growth factor, etc. [37,48–51]. Surface modification of PLGA, drug encapsulation methods and particle size, additives added during formulation, molecular weight of drug, ratio of lactide to glycolide moieties has strong influence on the release and effective response of formulated nanomedicines [52]. The acidic nature of PLGA monomers is not suitable for drugs or bioactive molecules [49,51]. However, the approaches to overcome these problems have been developed. For this PLGA nanomedicine formulation are blended with alginate, chitosan, pectin [53], poly(propylenefumarate) [54] polyvinylacohol [51,55], poly(orthoester), etc. [56]. The approval of PLGA has been granted by US Food and Drug Administration (USFDA) for human use and nanomedicines [57]. Many drugs of various diseases are formulated and commercialized in the market [40]. Many encapsulants have been successfully entrapped into/or adsorbed to PLGA nanoparticles. Some of the applications of PLGA-based nanomedicines which are effective against some common diseases are as follows (Table 1A). 3.1. Encapsulation of various anticancer drugs on PLGA nanoparticles PLGA is approved by FDA for therapeutic use in humans. Protocols have been optimized for PLGA nanoparticles synthesis and numerous cancer related drugs have been incorporated in PLGA [38]. These loaded nanoparticles protect poorly soluble and unstable payloads from the biological milieu and are small enough for capillary penetrations, cellular internalization and endosomal escape [37,58]. Furthermore, their surface is modified for targeted delivery of molecules to tumor or other tissues [59]. The larger size of PLGA nanoparticles is advantageous as multifunctional imaging and probes which incorporate encapsulated cancer drug, release, imaging, and targeting in a single nanoparticles platform [60]. The performance of these nanoparticles is not completely satisfactory and great effort is needed to improve its physiochemical

properties and synthesis process. The properties of nanoparticles as precursor of good nanomedicine are particle size, size distribution, surface morphology, surface chemistry, surface charge, surface adhesion, surface erosion, interior porosity, drug diffusivity, drug encapsulation efficiency, drug stability, drug release kinetics and hemodynamic. The surface charge of the nanoparticles is important for the cellular internalization of the NPs, clustering in blood flow, adherence, and interaction with oppositely charged cells membrane [34]. PLGA nanoparticles are frequently used for the encapsulation of various cancer related drugs and their successful delivery in vivo. The cancer related drug paclitaxel, doxorubicin, 5-fluorouracil, 9-nitrocamptothecin, cisplatin, triptorelin, dexamethasone, xanthone, etc., have been successfully encapsulated on PLGA nanoparticles (Table 1A). The mechanism of action of these drugs, encapsulation mechanism, encapsulation efficiency, peculiar characteristic for encapsulation and drug release mechanisms of this cancer therapeutics are briefly described. 3.1.1. 9-Nitrocamptothecin 9-Nitrocamptothecin (9-NC) (derivative of camptothecin) and related analogues are a promising family of anticancer agents with a unique mechanism of action, targeting the nuclear enzyme topoisomerase-I. Unfortunately, all camptothecin derivatives undergo a pH dependent rapid and reversible hydrolysis from closed lactone ring to the inactive hydroxyl carboxylated form with loss of antitumor activity. The delivery of lipophilic derivatives of 9-NC is quite challenging because of instability at biological pH and its low water solubility. PLGA has been used to encapsulate 9-NC successfully by nanoprecipitation methods having more than 30% encapsulation efficiency with its complete biological activity and without disturbing lactone ring [61]. The in vitro drug release profile showed a sustained 9-NC release upto 160 h indicating the suitability of PLGA nanoparticles in controlled 9-NC release (Table 1A). 3.1.2. Paclitaxel Paclitaxel (commercially available as taxol) interferes with the normal function of microtubule breakdown by binding with ␤subunit of tubulin. This drug promotes the polymerization of tubulin causing cell death by disrupting the dynamics necessary for cell division. This drug has neoplastic activity against primary ovarian carcinoma breast and colon cancers. It is one of the potent anticancer agent but less useful for clinical administration due to its poor solubility. PLGA intermingled with vitamin E, and tocopheryl

6


polyethylene glycol succinate (TPGS) has been used to encapsulate by solvent evaporation/extraction methods and in vitro controlled release of this drug [62]. This formulation has shown reasonably good activity and much faster administration in comparison to traditional formulation [63]. Using some additive to the PLGA nanoparticles 100% drug encapsulation efficiency was achieved with its full antitumor activity [63]. The release kinetics include 50% burst release within 24 h and slow release for one month in vitro [24]. It has also been demonstrated that incorporation of paclitaxel in the PLGA nanoparticles strongly enhances its antitumoral efficacy as compared to free drug. This effect being more relevant for prolonged incubation times with cells [63]. 3.1.3. Cisplatin Cisplatin is known to crosslink DNA molecule in several ways to interfere cell division by mitosis. The damaged DNA elicits DNA repair mechanism. Cisplatin is a very potent anticancer drug but the full therapeutic exploitation of cisplatin is limited due to its toxicity in healthy tissues, including renal and auditory toxicity, nausea and vomiting [64]. The selective delivery (targeting) of cisplatin to tumor cells would significantly reduce drug toxicity, and improve its therapeutic index. The cisplatin have been encapsulated on PLGA–mPEG nanoparticles prepared by double emulsion methods. PLGA–methoxy(polyethylene glycol) (mPEG) nanaoparticles revealed prolonged drug residence in blood upon intravenous administration [65]. However, at the targeted site PLGA–mPEG nanoparticles encapsulated with cisplatin exhibited rapid degradation and sustained release. These characteristics help in preventing the tumor growth. 3.1.4. Xanthones Xanthones are natural, semisynthetic and heterocyclic compounds with the dibenzo-␥-pyrone framework. Xanthone molecules having a variety of substituents on the different carbons constitute a group of compounds with a broad spectrum of biological activities [66]. These molecules inhibited the nitric oxide production from the macrophages and thus have strong inhibitory action on human cancer cell line growth. Xanthone loaded PLGA nanospheres have been prepared by solvent displacement methods. Nanoincorporation of these poorly water soluble compounds affords the preparation of formulations with higher concentrations of xanthones. Developed formulations were shown to be physically stable for 3–4 months. The release profile of xanthone from nanocapsules suggests the existence of an interaction of the drug with the polymer [67]. 3.1.5. Rose bengal Rose bengal is frequently employed as sensitizer to produce singlet oxygen. This property of rose bengal is used for the treatment of melanoma cancer cells because this drug is taken up by the tumor cells only and localized in the lysosomes. This molecule has been successfully entrapped into PLGA nanoparticles by interfacial deposition method. The low drug loading was attributed to the hydrophilicity of drug and small size of nanoparticles. Drug release was biphasic with 50% release measured within 30 min in serum. The half-life of nanoencapsulated rose bengal in the blood stream was greatly extended [68]. 3.1.6. Triptorelin Triptorelin is a decapeptide analog of lutenizing releasing hormone (LRH) used for the treatment of sex hormone dependent tumors. Triptorelin reduces the production of leutenising hormone to significantly reduce the levels of testosterone production and accumulation. This may result in shrinkage or slowing down the growth of the cancer. In order to optimize the treatments by triptorelin, maintenance of constant plasma levels of drug

for prolonged time periods is required. Triptorelin loaded PLGA nanospheres have been prepared by double emulsion solvent evaporation method with encapsulation efficiency varying from 4% to 83% [69]. High encapsulation efficiency was explained by an ionic interaction occurring between the peptide and the copolymer. This shows that release of peptides from PLGA nanospheres is also governed by the affinity of the encapsulated molecule versus the polymer. 3.1.7. Dexamethasone Dexamethasone is often administered before antibiotics in cases of bacterial meningitis. It acts to reduce the inflammatory response of the body to killed bacterial population by the antibiotics, thus improving prognosis and outcome. Dexamethasone causes inhibitory effect on leukocytes infiltration at the inflammatory site. It is a poorly soluble and crystalline corticoid that has been used for the treatment of diabetic macular edema administered as an implant. Dexamethasone has been incorporated into PLGA nanoparticles by solvent evaporation method [22]. The highest drug loading was obtained using 100 mg PLGA (75:25) in a mixture of acetone–dichloromethane 1:1 (v/v) and 10 mg of dexamethasone. The drug was completely released from this formulation after 4 h of incubation at 37 ◦ C in vitro (Table 1A). 3.2. Encapsulation of diabetes drugs (insulin) on PLGA nanoparticles Four subcutaneous insulin injections per day are required to maintain serum glucose levels according to current dosage regimens. However, to maintain the long-term complications of diabetes mellitus a specific formulation of 1.6% zinc insulin in poly(d,l-lactide-co-glycolide) (PLGA) with fumaric anhydride oligomer and iron oxide additives has been found effective for oral administration. This formulation is shown to have 11.4% of the efficacy of intraperitoneally delivered zinc insulin and is able to control plasma glucose levels when faced with a simultaneously administered glucose challenge [70]. The recently formulated insulin—loaded nanoparticles of PLGA is used to maintain the integrity of insulin during formulation and delivery. When nanoparticles were prepared by solvent evaporation technique, higher encapsulation efficiency of 75% is observed with a 5% target loading. The yield of nanoparticles prepared by different methods varied from 55% to 99%. The nanoparticles prepared by solid/oil/water method gave the burst effect and the sizes of the nanoparticles and encapsulation efficiency were reduced up to 223–243 nm and 0.3–12% respectively [70]. 3.3. Encapsulation of psychotic drugs (haloperidol) on PLGA nanoparticles Haloperidol is a primitive antipsychotic drug used for the treatment of schizophrenia and more acutely in the treatment of acute psychotic states. The delirium decanoate ester is used as a long acting injection given every week to patient with schizophrenia. Haloperidol possesses a strong activity against delusions and hallucinations, most likely due to an effective dopaminergic receptor blockage in the mesocortex and the limbic system of the brain. PLGA has been used for encapsulation and for extended controlled release of haloperidol [21]. PLGA end-groups have a strong influence on haloperidol incorporation efficiency and its release from PLGA nanoparticles. The hydroxyl terminated PLGA (uncapped) nanoparticles have a drug incorporation efficiency of more than 30% as compared to only 10% with methyl terminated PLGA (capped) nanoparticles. Haloperidol incorporation into PLGA with –COOH end-groups (uncapped) is three times more than in capped PLGA. Uncapped PLGA shows a lower initial burst release

Table 1B PLA biodegradable polymeric nanoparticles for drug delivery. Polymer

Encapsulation efficiency

Synthesis methods


Release mechanism

Haloperidol

30%

Solvent evaporative method

Slow release of drug up to 4 days

Diffusion

Hemoglobin

87.9%

Double emulsion method

Less macrophage uptake

Diffusion

Spray drying

Slow drug release up to 50 h Oral absorption was improved

Diffusion

Dexamethasone

6%

Surface modification

References

[21]

PEG

Reduced lever accumulation

[123] [124]

Ellagic acid

50%

Emulsion diffusion evaporation method

Protein-C

86.3%


Zidovudine BSA

55% 75.6%

Solvent evaporation Double emulsion method

Oridonin

91.88%

Modified spontaneous emulsion solvent diffusion method

Neurotoxin-I

35.5%


Brain delivery of NT-1 enhanced

Diffusion

Savoxepine

95%

Salting out

Controlled drug release up to 1 week

Diffusion

PEG

Progesterone

70%

Solvent evaporation

Diffusion

PEG

Release of protein C seems to increase with the hydrophilic character of PLA Less phagocytosis Prolonged blood circulation time than free drug Slow drug release up to 72 h

In vivo

Diffusion and degradation

Nps protected the cyclosporin induced nephrotoxicity in rats

[125]

[36]

PEG Diffusion of the entrapped protein and poly degradation Diffusion

Avoids phagocytosis Internalization by both NIH-3T3 and caco-2-cell lines Stable and high concentration of Oridonin in liver, lung and spleen and distribution in kidney decreased Brain delivery of NT-1-NPs (i.n.) was shorter than that for NT-1 –Nps (i.v.) Sustained plasma levels after intramuscular and intravenous injection

[126] [113]

[77]

[23]


Polylactic acid (PLA)

Structure of polymer Encapsulant

[19]

[75]

7

8


and a longer period of haloperidol release as compared to capped PLGA [21]. 3.4. Encapsulation of hormones (estradiol) on PLGA nanoparticles Estradiol is most potent natural estrogen and mainly prescribed for postmenopausal symptoms as a part of hormone replacement therapy either alone or in combination with another female hormone progestin. Also it has been found that estradiol intake may decrease the risk of Alzheimer’s disease by promoting the growth and survival of cholinergic neurons and reducing cerebral amyloid deposition. Estradiol not only has a critical impact on reproductive and sexual functioning, but also affects other organs including bone structure. Estradiol encapsulated PLGA nanoparticles have been prepared by emulsion diffusion evaporation method [52]. Change in molecular weight and copolymer composition of PLGA produced different release behaviours observed during in vitro and in vivo. In vitro drug release decreases with increase in molecular weight and lactide content of PLGA. Zero order release was obtained with low molecular weight PLGA, while high molecular weight and different copolymer composition followed square root of time dependent release (Table 1A). Thus estradiol loaded PLGA nanoparticles can be effective in improving the oral bioavailability and decreasing the dosage frequency, thereby minimizing the dose dependent adverse effects and maximizing the patient’s compliance [52]. 3.5. Encapsulation of tetanus drugs on PLGA nanoparticles Tetanus toxoid (TT) plays an important role in preventing the skin from being penetrated by the tetanus bacteria. The development of single dose vaccine, it is imperative to release immunoreactive antigen from polymer particles as well as make them more immunogenic either by delivery to macrophages or immunizing along with an adjuvant for better presentation of antigen to cells. The limited success is reported to develop single shot vaccine for tetanus toxoid (TT) on PLGA entrapped nanoparticles. These nanotoxoids are able to develop immune responses from polymer entrapped antigen and reduce the adjuvant effect. PLGA entrapped tetanus toxoid nanoparticles have been prepared by solvent evaporation method [16]. Immunization with polymer particles encapsulating stabilized TT elicited anti-TT antibody titres, and were higher than those obtained with saline TT. Immunization with nanoparticles along with alum resulted in very high and early immune response [16]. 4. Polylactic acid (PLA) PLA (polylactic acid) polymer is biocompatible and biodegradable material which undergoes scission in the body to monomeric units of lactic acid as a natural intermediate in carbohydrate metabolism. PLA nanoparticles have been mostly prepared by solvent evaporation, solvent displacement [71] salting out [42] and solvent diffusion. The salting out procedure is based on the separation of a water miscible solvent from aqueous solution by adding salting out agent like magnesium chloride, calcium chloride, etc. The main advantage of salting out procedure is that it minimizes stress to protein encapsulants. 4.1. Encapsulation of psychotic drugs (savoxepine) on PLA nanoparticles Savoxepine acts via selective limbic dopamine D2 receptor blockade [72]. Savoxepine loaded nanospheres have been prepared by salting out procedure [19]. Drug loading reached upto 16.7%

with encapsulation efficiency as high as 95%. In vitro release studies demonstrated that this type of drug carriers allows extended delivery of the drug over more than one week. In vivo, nanoparticles loaded with neuroleptic compound savoxepine were able to provide sustained plasma levels after intramuscular and intravenous injection. Intramuscularly injected nanoparticles remained at the site of injection, whereas intravenously injected nanoparticles were located mostly in the macrophages (MPS) [19]. The PEG 6000 and PEG 20000 have been used to make an additional coating during the preparation and encapsulation of PLA nanoparticles (Table 1B). In vitro, these coatings provided a protective barrier against extensive uptake by human monocytes, at least in plasma. Analysis of plasma proteins adsorbed on nanoparticles and in vitro experiments on isolated cells revealed some differences between the opsonization process of plain and coated nanoparticles [19]. 4.2. Encapsulation of restenosis drugs (tyrphostins) on PLA nanoparticles The major complication of precutaneous transluminal coronary angioplasty (known as restenosis) is responsible for the 35–40% long-term failure of coronary revascularization. The neointimal formation (a morphological substrate of restenosis) is dependent on smooth muscle cells (SMC) proliferation and migration. Signal transduction through the platelet-derived growth factor (PDGF) and PDGF receptors system is involved in the process of post-angioplasty restenosis. The unsuccessful attempts to control restenosis by systemic pharmacological interventions have prompted many researchers to look for more promising therapeutic approaches such as local drug delivery. The tyrosine kinase receptors participate in transmembrane signaling, and the intracellular tyrosine kinases take part in signal transduction within the cell including the nucleus. Tyrphostins are low molecular weight inhibitors of protein tyrosine kinases [73]. Thus inhibition of the autocrine/paracrine loop of PDGF and bFGF (basic fibroblast growth factor) could be achieved through inhibition of growth factors receptors associated tyrosine kinase activity. The intraluminal delivery of the drug tyrphostin is very poor towards the transmembrane signaling. Local intraluminal delivery of tyrphostins inhibitors (commercial name is AG-1295) loaded PLA nanoparticles to the injured rat carotid artery had no effect on proliferative activity in medial and neointimal compartments of angioplastisized arteries, indicating a primary antimigration effect of AG-1295 on medial smooth muscle cells [74]. 4.3. Encapsulation of hormones (progesterone) on PLA nanoparticles Progesterone is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy (supports gestation) and embryogenesis of humans and other species. Progesterone-loaded PLA–PEG–PLA nanoparticles have been prepared by solvent evaporation method [75]. The drug trapping efficiencies were around 70 ± 5% with size 260–320 ± 100 nm. This size difference of PLA nanoparticle is due to surface modification by various molecular weight (60–120 kDa) PEG and their percent content (0–15% w/w). The in vitro release of PLA–PEG–PLA nanoparticles confirms the maximum release in 0.1% (w/w) polysorbate 80 media than PBS. However, the bigger nanoparticles generated by the different molecular weight PEG have higher in vitro release than non-modified PLA nanoparticles [75]. The amount of drug release increases as the PEG content and molecular weight of PLA–PEG–PLA copolymers increased and the total molecular weight of copolymers of nanoparticles decreased. The initial burst of drug release was reduced by removing the low molecular weight fraction

Table 1C PCL biodegradable polymeric nanoparticles for drug delivery. Polymer

Encapsulant

Encapsulation efficiency

Synthesis methods


Tamoxifen

90%

Solvent displacement

Preferential tumor targeting and circulating drug reservoir

Clonazepam

72.6–95.1%

Solvent evaporation method

Saquinavir

60%

Solvent displacement method

Drug release behaviour can be modulated by introducing thermo sensitive polymers Higher Intracellular saquinavir concentrations

Taxol

20.79%

Micelles

Higher taxol loading

Insulin

96%

Docetaxel

90%

Vinblastine

48%

Nanoprecipitation method Emulsion method

Release mechanism


In vivo

References

Pluronics

Increased level of accumulation of the drug within tumor with time and extended their presence in circulation

[12]

Diffusion

Diffusion

[79]

PEO

MePEG

Preservation of insulins’ biological activity Higher antitumor effect

Diffusion

Slow drug release up to 20 days

Diffusion

Diffusion

Rapid cellular uptake of rhodamine-123 encapsulated PEO–PCL nanoparticles was observed in THP-1 cells Decreased fasted glycemia in a dose dependent manner and nanoparticle strongly adhered to intestinal mucosa

[108]

[30]

[26] MePEG

Effectively kills B16 cells

[127]

Breast cancer cell line (MCF-7) showed efficient uptake

[128]


Poly-␧-caprolactone (PCL)


9

10


from the polymer. PLA–PEG–PLA nanoparticles release appears to be controlled by the hydrophilic segments introduced into the hydrophobic parent PLA polymer [75]. 4.4. Encapsulation of oridonin on PLA nanoparticles Oridonin (natural diterpenoid) induced growth arrest and apoptosis of cells from lymphoid malignancies in association with inhibition of NF-␬B and down-regulation of Bcl-2 family proteins [76]. The success of its clinical application is greatly limited by its poor water solubility and low therapeutic index. Oridonin-loaded poly(lactic acid) nanoparticles were prepared by modified spontaneous emulsion solvent diffusion method [77]. The entrapment efficiency and actual drug loading of the nanoparticles were as much higher as 91.88 ± 1.83% and 2.32 ± 0.05%, respectively. The results of pharmacokinetics demonstrated that oridonin encapsulated on PLA nanoparticles were remarkably effective for oridonin to prolong blood circulation time. The stable and high concentration of oridonin in liver, lung and spleen are reported after the intravenous administration of oridonin-PLA-nanoparticle, while its distribution in heart and kidney are significantly decreased [77] (Table 1B).

of polymer. The liver is primary site of accumulation for the drugloaded nanoparticles after intravenous administration. Nearly upto 26% of the total activity could be recovered in tumor at 6 h of postinjection for PEO-modified nanoparticles. PEO–PCL nanoparticles exhibited significantly increased level of accumulation of the drug within tumor with time as well as extended their presence in the systemic circulation than the controls (unmodified nanoparticles or the solution form) [78] (Table 1C). 5.1.2. Taxol Polyethylene glycol–PCL amphiphilic block copolymeric nanospheres containing taxol are reported to show promising anticancer activity [30]. The nanospheres having a relatively high drug loading of more than about 20% was reported. The acute toxicity study confirms the biocompatibility of nanosphere itself. It was reported that this mPEG/PCL diblock copolymeric nanospheres system could be potentially useful as a novel delivery system for anticancer drug taxol having outer shell of mPEG and the hydrophobic inner core of PCL. In addition, considering the extremely lipophilic characteristics of taxol, this mPEG/PCL nanosphere system with high taxol loading content and suspended properties in water could be useful for the delivery of taxol [78] (Table 1C).

4.5. Encapsulation of protein (BSA) on PLA nanoparticles A tadpole-shaped polymer mono(6-(2-aminoethyl) amino-6deoxy) ␤-cyclodextrin-PLA (CDen-PLA) was used to encapsulate the BSA successfully by double emulsion method and nanoprecipitation method [78]. The encapsulation efficiency was upto 71.6%. The results showed that this new copolymer could load BSA effectively and BSA remains stable after it was released from the nanoparticles. This report opens the door for the successful encapsulation and delivery of various disease related proteins for protein therapy [78] (Table 1B). 5. Poly-␧-caprolactone (PCL) PCL (poly-␧-caprolactone) is degraded by hydrolysis of its ester linkages in physiological conditions (such as in the human body) and has therefore received a great deal of attention for use in drug delivery. In particular, it is especially interesting for the preparation of long-term implantable devices, owing to its degradation slower than that of polylactide. PCL nanoparticles have been prepared mostly by nanoprecipitation, solvent displacement and solvent evaporation. We are describing below some of the molecules that have been successfully incorporated into PCL nanoparticles to increase their therapeutic value (Table 1C). 5.1. Encapsulation of anticancer drugs on PCL nanoparticles 5.1.1. Tamoxifen Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects [12]. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. The drug tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Thus it prevents proliferation of pre-cancerous cells and distinguished from dividing cells. This molecule do not cause cell death, it means tamoxifen is cytostatic rather than cytocidal [78]. Tamoxifen itself is a prodrug having relatively little affinity for its target protein the estrogen receptor. Tamoxifen loaded polyethylene oxide (PEO) modified PCL were prepared by solvent displacement method. About 90% drug encapsulation efficiency have been achieved when tamoxifen were loaded 10% by weight

5.2. Encapsulation of diabetes drugs (insulin) on PCL nanoparticles Nanoparticles prepared with a blend of a biodegradable polyester PCL and a poly cationic non-biodegradable acrylic polymer have been used as a drug carrier for oral administration of insulin [26]. The rate of encapsulation of insulin was around 96%. When administered orally by force-feeding to diabetic rats, insulin nanoparticles decreased fasted glycemia in a dose dependant manner with a maximal effect observed with 100 IU/kg. These insulin–PCL nanoparticles also increases serum insulin levels and improved the glycemic response to an oral glucose challenge for a prolonged period of time. FITC–insulin-loaded nanoparticles strongly adhered to the intestinal mucosa and labeled insulin; either released and/or still inside nanoparticles. This was mainly taken up by the cells of Peyer’s patches. It is concluded that polymeric nanoparticles allows the preservation of insulin’s biological activity. In addition, the antidiabetic effect can be explained by the mucoadhesive properties of the polycationic polymer allowing the intestinal uptake of insulin [26] (Table 1C). 5.3. Encapsulation of clonezepam drugs on PCL nanoparticles Clonezepam acts in the brain by enhancing the effects of gamma aminobutyric acid GABA (brain chemical that is naturally calming). GABA is known to slow down or stop certain nerve signals in the brain. Poly(N-isopropylacrylamide)-b-poly(3caprolactone) (PNPCL) as block copolymers have been used to encapsulate hydrophobic drug clonezepam by solvent evaporation method [79]. The poly(N-isopropylacrylamide) block may compose hydrophilic corona of the PNPCL nanoparticles and act as temperature sensitive component. Owing to the amphiphilic character, the PNPCL block copolymers formed self-aggregated nanoparticles and such nanoparticles showed excellent potentials for drug carriers. Furthermore, the poly-N-isopropylacrylamide (PNiPAAm) shell showed temperature induced phase transition at slightly lower than physiological temperature with enhancement of nanoparticle hydrophobicities. Drug release test revealed that the formation of PNiPAAm hydrogel layers on the nanoparticle surfaces delayed the drug release patterns by acting as an additional diffusion barrier. Therefore, the introduction of thermosensitive polymers on poly-

Table 1D Gelatin, chitosan, and PAC biodegradable polymeric nanoparticles for drug delivery. Polymer

Gelatin

Poly-alkyl-cyano-acrylates (PAC) Poly(ethyl) cyanoacrylate

Encapsulant

Encapsulation Synthesis efficiency methods

Therapeutic improvements

Release mechanism

Paclitaxel

33–78%

Desolvation method

Biologically activity of paclitaxel is retained

Diffusion

Didanosine

72.5%

Double desolvation technique

Slow drug release up to 24 h

Diffusion

Chloroquine phosphate

15–19%

Reduced side effects

Diffusion

Insulin

72.8%

Solvent evaporation method Ionotropic gelation method

Oral absorption and oral bioactivity was increased

Diffusion

Sulphamethaxazole 39%

Solvent evaporation

Slow release up to 10 h

Diffusion

Cyclosporin A

73%

Ionic gelation method

Dissolution

Ammonium glycyrrhizinate

35%


BSA

92%


It was possible to achieve therapeutic concentration in external ocular tissues Oral absorption of ammonium glycyrrhizinate increased Slow drug release up to 4 weeks

Controlled release of the drug up to 10 h

Diffusion

Ftorafur

Anionic polymerization


Mannan

In vivo

References

[93] Paclitaxelloaded nanoparticles were active against human RT4 bladder transitional cancer cells [95] Higher accumulation of didanosine in brain [96]

Nanoparticles [89] adhere to intestinal epithelium and internalized by intestinal mucosa [129]

[90] cy A concentration were higher in cornea than conjuctiva

PEG Diffusion and polymer degradation

[88]

Diffusion

[130]

Lactic acid


Chitosan


[102]

11


[131] Permeate through rats skin in a period of 8 h

Inhibition in the[92] platelet aggregation

meric nanoparticles might be a useful approach to enhance and/or modulate clonezepam release patterns [79].

Interfacial polymerization 76.6% Indomethacin

Antiinflammatory activity have been increasing after nanoencapsulating indomethacin Improved transdermal delivery Polymerization Indomethacin

Encapsulant

Encapsulation Synthesis efficiency methods

Therapeutic improvements

Release mechanism


In vivo

References

12

5.4. Encapsulation of antifungal (amphotericin B) drugs on PCL nanoparticles Amphotericin B (AmB) associates with ergosterol, a membrane chemical of fungi, forming a pore that leads to potassium leakage and fungal cell death. Amphotericin B is believed to interact with membrane sterols to produce an aggregate that forms a transmembrane channel. Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl and amino groups stabilize the channel in its open form, destroying activity and allowing the cytoplasmic contents to leak out. PCL nanoparticles have been developed in order to study their ability to improve anti-leishmanial action of AmB with concomitant reduction in the toxicity associated with it [80]. Nanoencapsulated AmB was found to be 2–3 times more effective than free AmB in reducing parasite burden from Leishmania infected mice and also the side effects associated with AmB [80] (Table 1C). 6. Chitosan Chitosan is a modified natural carbohydrate polymer prepared by the partial N-deacetylation of crustacean derived natural biopolymer chitin. There are at least four methods reported [39] for the preparation of chitosan nanoparticles as ionotropic gelation, microemulsion, emulsification solvent diffusion and polyelectrolyte complex [39]. Ionotropic gelation is based on electrostatic interaction between amine group of chitosan and negatively charge groups of polyanion such as tripolyphosphate [81–83]. Chitosan is dissolved in acetic acid in the absence or presence of stabilizing agent. Polyanion was then added and nanoparticles were spontaneously formed under mechanical stirring [84]. In microemulsion method, a surfactant was dissolved in an organic solvent like n-hexane. Then chitosan in acetic acid solution and glutaraldehyde were added to surfactant/hexane mixture under continuous stirring at room temperature [85]. Polyelectrolyte complex (PEC) or self-assemble polyelectrolyte is a term to describe complexes formed by self-assembly of the cationic charged polymer and plasmid DNA. Mechanism of PEC formation involves charge neutralization between cationic polymer and DNA leading to a fall in hydrophilicity as the polyelectrolyte component self-assembly [86]. In this method nanoparticles are spontaneously formed after addition of DNA solution into chitosan dissolved in acetic acid solution under mechanical stirring at or under room temperature [86]. Several drug molecules are successfully encapsulated for their in vivo use (Table 1D).

Polymer

Table 1D (Continued )


6.1. Encapsulation of antihormonal (glycyrrhizin) drugs on chitosan nanoparticles Glycyrrhetic acid inhibit progesterone metabolism either indirectly by preventing the regeneration of triphosphopyridine nucleotide or directly by inhibiting the reduction of progesterone. Glycyrrhetic acid is an aglycone and an active metabolite of glycyrrhizin (GLZ) [87]. It shows various therapeutic effects such as anti-inflammatory, antitumorigenic and anti-hepatotoxic activities. GLA is considered to play an important role in the biological action of oral administration of GLZ because only GLA appears in the blood circulation after oral administration of GLZ. Chitosan nanoparticles have shown excellent capacity for the association of ammonium glycyrrhizinate [88]. Adding PEG decreases the encapsulation and reduces the positive charge. This surface modification by PEG has been achieved by co-synthesis of chitosan polymer


along with tripolyphosphate anions (TPP) and PEG by ionic gelation methods. These surface modifications decrease the positive charge, encapsulation efficiency and absorption with increases of the particle size. Thus in this particular case the surface modification is not so effective [88]. The release profile of ammonium glycyrrizinate from nanoparticles has an obvious burst effect and a slowly continuous release phase followed. The nanoparticle may improve the oral absorption of ammonium glycyrrhizinate [88]. 6.2. Encapsulation of insulin on chitosan nanoparticles Insulin was observed to be directly internalized by enterocytes in contact with intestine and retention of drugs at their absorptive sites by mucoadhesive carriers is a synergic factor [89]. Insulin loaded chitosan nanoparticle markedly enhanced intestinal absorption of insulin following oral administration. The hypoglycemia effect and insulinemia levels were significantly higher than that obtained from insulin solution and physical mixture of oral insulin and empty nanoparticles. The mechanism of insulin absorption seems to be a combination of both insulin internalization, probably through vesicular structures in enterocytes and insulin loaded nanoparticle uptake by cells of Peyers patches [89]. 6.3. Encapsulation of ocular (cyclosporin A) drugs on chitosan nanoparticles The ability of cyclosporin A (Cy A) to inhibit T-cell activation has been shown to have a role in the treatment of diseases such as nephrotic syndrome, refractory Crohn’s disease, ulcerative colitis, biliary cirrhosis, aplastic anemia, rheumatoid arthritis, myasthenia gravis, and dermatomyositis. Extensive investigation carried out over the last decade support the view that the local immunosuppression caused by Cy A is effective for the management of extra ocular disorders [90]. Despite the evidence that the target sites for the treatment of these diseases are the cornea and conjunctiva the Cy A delivery systems, so far investigated have not been successful. Chitosan nanoparticles loaded with Cy A can contact intimately with the corneal and conjunctiva surfaces, thereby increasing delivery to external ocular tissues without compromising inner ocular structures and systemic drug exposure. This helps to provide these target tissues with long-term drug levels [90]. 7. Gelatin Gelatin is extensively used in food and medical products and is attractive for use in controlled release due to its nontoxic, biodegradable, bioactive and inexpensive properties. It is a polyampholyte having both cationic and anionic groups along with hydrophilic group. It is known that mechanical properties, swelling behavior and thermal properties depend significantly on the crosslinking degree of gelatin. Gelatin nanoparticles can be prepared by desolvation/coacervation [91] or emulsion method [36]. Desolvation/coacervation is a process during which a homogeneous solution of charged macromolecules undergoes liquid–liquid phase separation, giving rise to a polymer rich dense phase at the bottom and a transparent solution above. The addition of natural salt or alcohol normally promotes coacervation and the control of turbidity/crosslinking that resulted in desired nanoparticles [91]. Many encapsulants have been successfully encapsulated into gelatin nanoparticles (Table 1D). 7.1. Encapsulation of BSA on gelatin nanoparticles Gelatin nanoparticles have been used for encapsulating BSA. These nanoparticles can absorb 51–72% of water. The release of

13

BSA from the gelatin nanoparticulate matrix follows a diffusioncontrolled mechanism [92]. 7.2. Encapsulation of anticancer drug (paclitaxel) on gelatin nanoparticles Paclitaxel-loaded gelatin nanoparticles have been reported by desolvation method [93]. Entrapped paclitaxel was present in an amorphous state, which has higher water solubility compared with the crystalline state. Identical, rapid drug release from nanoparticles was observed in PBS and urine with ∼90% released at 37 ◦ C after 2 h. The paclitaxel-loaded nanoparticles were effective against human bladder transitional cancer cells [93] (Table 1D). 7.3. Encapsulation of oligonucleotides on gelatin nanoparticles The ionic interaction based nanoencapsulation of double stranded oligonucleotides have been reported onto the surface of modified gelatin nanoparticles [94]. This formulation accomplished in an isoosmotic sodium chloride solution to confirm the reduced efficiency of loading process of the double stranded siRNA, and oligonucleotides in media with an accelerated ionic strength [94]. 7.4. Encapsulation of anti-HIV drug (didanosine) on gelatin nanoparticles The hydrophilic didanosine crosses very slowly to the blood–brain barrier (BBB). This molecule was encapsulated on mannan coated gelatin nanoparticles by desolvation method [95]. Didanosine was localized to a greater extent in the spleen lymph nodes and brain, respectively, after administration of mannan coated gelatin nanoparticles compared to that after injection in PBS [95] (Table 1D). 7.5. Encapsulation of antimalarial drug (chloroquine phosphate) onto gelatin nanoparticles Chloroquine, an antimalarial drug works by killing the different form of the malaria parasite that infects the red blood cells. The toxic effects of chloroquine phosphate (CP) consist of headache, drowsiness, visual disturbances, nausea and vomiting. To reduce these side effects, this molecule was encapsulated on Gelatin nanoparticles [96]. This nanomedicine effectively delivers CP via controlled diffusion optimally at physiological pH. The release of CP is inversely proportional to gluteraldehyde content in the nanoparticles [96] (Table 1D). 8. Poly-alkyl-cyano-acrylates (PAC) The biodegradable as well as biocompatible poly-alkylcyanoacrylates (PAC) are degraded by esterases in biological fluids and produce some toxic products that will stimulate or damage the central nervous system. Thus this polymer is not authorized for application in human [97]. However, PAC nanoparticles are prepared mostly by emulsion polymerization, interfacial polymerization [42] and nanoprecipitation for drug delivery and nanoformulation. Emulsion polymerization is classified into two categories based on the use of an organic or aqueous continuous phase. The continuous organic phase methodology involves the dispersion of monomer into an emulsion or inverse emulsion, or into a material in which the monomer is not soluble. In the aqueous continuous phase the monomer is dissolved in a continuous phase that is usually an aqueous solution, and the surfactants or emulsifiers are not needed [42]. In interfacial polymerization, the cyanoacryalate monomer and drug was dissolved in a mixture of an oil and absolute ethanol.

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This mixture was then slowly extruded through a needle into a well stirred aqueous solution, with or without some ethanol containing surfactant. An advantage of interfacial polymerization technique is high efficiency drug encapsulation [98] (Table 1D). 8.1. Encapsulation of antibacterial (ampicillin) on poly-alkyl-cyanoacrylates nanoparticles Ampicillin acts as a competitive inhibitor of the cell wall maker enzyme transpeptidase. Ampicillin was found to be mechanically entrapped in the polyisobutylcyanoacrylate (PIBC) nanoparticles, as no modification in molecular weight distribution of the gel permeation chromatography was observed after loading with ampicillin. The release of antibiotic ampicillin was homogeneous [99]. 8.2. Encapsulation of anti-inflammatory (indomethacin) drugs on poly-alkyl-cyanoacrylate nanoparticles Indomethacin is a non-selective inhibitor of cyclooxygenase (COX) 1 and 2 enzymes that participate in prostaglandin synthesis from arachidonic acid. The indomethacin inhibits the production of prostaglandin in the stomach and intestines which maintain the mucous lining of the gastrointestinal tract. Indomethacin has been encapsulated into PIBC nanoparticles and found stable up to 12 months [100]. The indomethacin content of the freezedried nanocapsules and in the suspension form was decreased by 52.8% and 17.5% respectively. Compared to free indomethacin the anti-inflammatory activity (10 times) and the inhibition of platelet aggregation have been increased after nanocapsulating indomethacin. However, PIBC nanocapsules also showed an inhibition in the platelet aggregation because of their isobutylcyanoacrylate content [100] (Table 1D). 8.3. Encapsulation of various anticancer drugs on poly-alkyl-cyanoacrylate nanoparticles The polybutylcyanoacrylate (PBC) encapsulated doxorubicin nanoparticles have been reported to increase 60-fold in the brain after coated with polysorbate 80 [101]. Ftorafur is a type of substance being used in the treatment of cancer. It is a combination of tegafur and uracil. The tegafur is taken up by the cancer cells and breaks down into 5-FU, a substance that kills tumor cells. The uracil causes higher amounts of 5-FU to stay inside the cells and kill them [102]. Poly-ethyl-2-cyanoacryalte (PE-2-CA) and PBC nanospheres were used to encapsulate ftorafur [Tegafur, 5-fluoro-1-(tetrahydro2-furyl) uracil], a broad spectrum antitumor drugs. With respect to the release profiles, ftorafur surface adsorption onto nanospheres led to a very rapid drug release in sink conditions. However, the drug incorporation into the nanoparticles permitted a larger loading and a slower ftorafur release [102] (Table 1D). 9. Modification of surface properties Polymeric nanoparticles have been characterized by their morphology and polymer composition in the core and corona. The drug molecule is either conjugated to the surface of the nanoparticles or encapsulated and protected inside the core (Fig. 1). The unique sizes of nanoparticles are amenable to surface functionalization or modification to achieve desired characteristics. This was achieved by various methods to form the corona to increase drug retention time in blood, reduction of nonspecific distribution and target tissues or specific cell surface antigens with targeting ligands (peptide, aptamer, antibody and small molecule) [20]. Different material/particles are used for the preparation of nanoparticles leading to a distinction in surface properties. The nanoparticles

surface modification is important to introduce drugs in the blood stream for “stealth” invisibility of the body’s natural defense system [103]. The mononuclear phagocytic system (MPS) eliminates them from the blood stream efficiently unless the particles are modeled to escape recognition. Longer circulation time increases the probability for the nanoparticles to reach their target. Small particles (