ReviewBiodegradable polymeric nanoparticles as drug delivery devices
Introduction
Over the past few decades, there has been considerable interest in developing biodegradable nanoparticles (NPs) as effective drug delivery devices. Various polymers have been used in drug delivery research as they can effectively deliver the drug to a target site and thus increase the therapeutic benefit, while minimizing side effects [1]. The controlled release (CR) of pharmacologically active agents to the specific site of action at the therapeutically optimal rate and dose regimen has been a major goal in designing such devices. Liposomes have been used as potential drug carriers instead of conventional dosage forms because of their unique advantages which include ability to protect drugs from degradation, target the drug to the site of action and reduce the toxicity or side effects [2]. However, developmental work on liposomes has been limited due to inherent problems such as low encapsulation efficiency, rapid leakage of water-soluble drug in the presence of blood components and poor storage stability. On the other hand, polymeric NPs offer some specific advantages over liposomes. For instance, NPs help to increase the stability of drugs/proteins and possess useful CR properties.
Nanoparticles generally vary in size from 10 to 1000 nm. The drug is dissolved, entrapped, encapsulated or attached to a NP matrix and depending upon the method of preparation, nanoparticles, nanospheres or nanocapsules can be obtained. Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed. In recent years, biodegradable polymeric NPs have attracted considerable attention as potential drug delivery devices in view of their applications in the CR of drugs, their ability to target particular organs/tissues, as carriers of DNA in gene therapy, and in their ability to deliver proteins, peptides and genes through a peroral route of administration [3], [4].
Some general aspects on micro- and nanoparticles have been reviewed earlier [1], [5], [6], [7], [8], [9], [10], [11]. A majority of these reviews have dealt with the NPs of poly(d,l-lactide), poly(lactic acid) PLA, poly(d,l-glycolide) PLG, poly(lactide-co-glycolide), PLGA, and poly(cyanoacrylate) PCA. The present review details the latest developments on the above mentioned polymers as well as NPs based on chitosan, gelatin, sodium alginate and other hydrophilic/biodegradable polymers. Surface modification aspects are also covered in more detail. The PLA, PLG and PLGA polymers being tissue-compatible have been used earlier as CR formulations in parentral and implantation drug delivery applications [12], [13], [14]. In addition, poly(ϵ-caprolactone), PCL, which was first reported by Pitt et al. [15], [16] for the CR of steroids and narcotic antagonists as well as to deliver opthalmic drugs [17], and poly(alkylcyanoacrylate), PACA, are now being developed as NPs. In addition, less frequently used polymers like poly(methylidene malonate) [18], gelatin [19], chitosan [20] and sodium alginate [21] will also be included in this review. The important published literature within the period 1990–2000 is critically reviewed. The review does not cover the entire literature within this period, but the reader is advised to go to the original literature in order to get more details.
Section snippets
Preparation of nanoparticles
Conventionally, NPs have been prepared mainly by two methods: (i) dispersion of the preformed polymers; and (ii) polymerization of monomers.
Drug loading
A successful NP system may be the one, which has a high loading capacity to reduce the quantity of the carrier required for administration. Drug loading into the NPs is achieved by two methods: one, by incorporating the drug at the time of NP production or secondly, by adsorbing the drug after the formation of NPs by incubating them in the drug solution. It is thus evident that a large amount of drug can be entrapped by the incorporation method when compared to the adsorption [76], [77].
Drug release
Drug release from NPs and subsequent biodegradation are important for developing the successful formulations. The release rates of NPs depend upon: (i) desorption of the surface-bound/adsorbed drug; (ii) diffusion through the NP matrix; (iii) diffusion (in case of nanocapsules) through the polymer wall; (iv) NP matrix erosion; and (v) a combined erosion/diffusion process. Thus, diffusion and biodegradation govern the process of drug release.
Methods to study the in vitro release are: (i)
Protein adsorption and phagocytosis of NPs
Plasma protein adsorption and phagocytosis of NPs is a subject that has been widely studied in recent years. When the NPs are administered intravenously they are easily recognized by the body immune systems, which are then cleared from the circulation. Apart from the size of NPs, their surface hydrophobicity determines the amount of adsorbed blood components, mainly proteins (opsonins). These will determine the in-vivo fate of NPs [98], [99]. Binding of these opsonins onto the surface of NPs,
Delivery of proteins and peptides using NPs
Peptide drugs are attracting, as their role in physiopathology is better understood and because of the progress made in biotechnology and bioengineering. Particularly, the development of DNA-recombinant technology has made these compounds available on large scale than in the past. However, the use of peptide in medicine is partly limited by their rapid degradation by proteolytic enzymes in the gastrointestinal tract; thus, they need to be administered through the parentral route. The biological
Conclusions
The use of biodegradable polymers for the CR of therapeutic agents is now well established. Although currently there are only a small number of commercially available products that utilize this technology (e.g., Lupron Depot®), these polymers have great utility for the CR of several drugs like vaccines, human growth hormone, insulin, anti-tumor agents, contraceptives and also vaccines. Long circulation of drugs in the body is the key in successful drug delivery and drug targeting to the site of
Acknowledgements
We immensely thank the Council of Scientific and Industrial Research, New Delhi, India [Grant # 80(0025)97/EMR-II] for a major financial support of this study. Dr. Walter E. Rudzinski thanks the Southwest Texas State University, San Marcos for a research enhancement grant. We also thank Dr. M.I. Aralaguppi for his assistance.
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