Review
Biodegradable polymeric nanoparticles based drug delivery systems

https://doi.org/10.1016/j.colsurfb.2009.09.001Get rights and content

Abstract

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.

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], [8], [9], [10], [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], [15], [16], [17], [18], [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], [22], [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 (nano-drug) 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 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.

Section snippets

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

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

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

Poly-ɛ-caprolactone (PCL)

PCL (poly-ɛ-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

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]

Gelatin

Gelatin is extensively used in food and medical products and is attractive for use in controlled release due to its non-toxic, 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

Poly-alkyl-cyano-acrylates (PAC)

The biodegradable as well as biocompatible poly-alkyl-cyanoacrylates (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

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

Drug loading and release mechanisms

A successful nanoparticle system may be the one which has high loading capacity to reduce the quantity of the carrier required for administration. Drug loading into nanoparticles is achieved by two methods: one by incorporating the drug at the time of nanoparticle production and second by adsorbing the drug after the formation of nanoparticles by incubating them in the drug solution [37]. Drugs can be loaded onto nanoparticles by adding them to a solution that contains previously prepared

Conclusion

Nanoparticulate drug delivery systems seem to be a viable and promising strategy for the biopharmaceutical industry. They have advantages over conventional drug delivery systems. They can increase the bioavailability, solubility and permeability of many potent drugs which are otherwise difficult to deliver orally. Nanoparticulate drug delivery systems will also reduce the drug dosage frequency and will increase the patient compliance. In near future nanoparticulate drug delivery systems can be

Acknowledgements

Authors are thankful to Dr. P.S. Ahuja, Director, IHBT for his valuable suggestions during writing of this article. The IHBT communication number of this article is 0998. Financial assistance from Council of Scientific and Industrial Research (CSIR) and Department of Science and Technology (DST), Government of India is genuinely acknowledged. Thanks to Mr. Jaykant Yadav CFTRI Mysore for editing and valuable suggestions.

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