Drug Delivery Applications Of Nanogels

Despite availability of several potent agents against various diseases, their effective delivery remains a major challenge. Several issues such as solubility, stability, specificity, sustained availability, penetrability across anatomical and physiological barriers, nonspecific toxicity, and so on, limit the successful transformation of these agents into drugs. Recent advances in nanotechnology offer many strategies to address the various problems associated with drug delivery. Nanostructures, due to their smaller size, can effectively shuttle therapeutics across different physiological and anatomical barriers.

Properties And Applications Nanogels
Figure 6.22. Transmission electron microscopic image of NIPAM-based nanogel after 3 months' storage.

The strategies that are being pursued are active targeting by modifying and func-tionalizing the surface of nanoparticle with tissue-specific antibodies or ligands. In passive targeting, the advantage of leaky vasculature associated with inflammatory milieu or in tumor is explored. However, the challenge in targeting is that nanoparticles attract the natural body defense system and hence are easily identified and taken up by the reticuloendothelial system. Therefore, successful nanostructure design requires assembly of appropriate surface characteristics as well as targeting ligands to achieve long systemic circulation and subsequent interactions with the receptors in the target tissue [245]. Nanogel formulations provide a better platform for designing of nanocarri-ers because of their three-dimensional cross-linkage structure with hydrophilic surface properties that prevent their clearance by the reticuloendothelial system. In addition, nanogels demonstrate unique properties, such as the ability to trap biomolecules inside the gel structure and rapidly respond to an external stimulus [246]. Due to these inherent qualities, nanogels have been investigated for protein and gene delivery applications [15,17,68-70,230]. Recent studies using novel photosensitive nanogels have demonstrated increase molecular chaperone-like activity upon photostimulation [133]. Similarly, the other group has shown improved thermal stability of the enzyme associated with artificial chaperons by using nanogels [247]. Since many drugs act as protagonists or antagonists to different chemicals in the body, a delivery system that can respond to the concentrations of certain molecules in the body is invaluable [248]. Yamagat et al. [249] demonstrated that pH-sensitive hydrogels protect insulin from gastric and intestinal enzymes.

Recently, there has been significant interest in developing nonviral vectors for synthetic vaccines designed to prime the adaptive immune system that are sought for a broad range of infectious diseases and for the treatment of cancer in both prophylactic and therapeutic settings [250-252]. However, many obstacles associated with the successful delivery of synthetic vaccines remain such as antigen loading capacity, maintaining the integrity of encapsulated proteins, and minimizing the nonspecific antigen-antibody reaction. Therefore, the delivery system that can effectively carry the protein antigens to antigen-presenting cells is most desirable. The feasibility of achieving these goals has been demonstrated using submicron-sized hydrophilic particles, which were loaded with high doses of protein [253].

One other important area of research where these nanogels can be effectively used is in the regenerative medicine. The major challenge is how to achieve significant expression of genes in highly compromised injured tissue surrounded by inflammatory environment [254]. Although delivery of genes encoding therapeutic protein is an alternative for outright delivery of protein, stability of plasmid DNA is not much different compared to proteins. The successful therapeutic gene delivery for tissue engineering requires a system that can provide a control over the DNA release, facilitate cellular uptake of DNA, maintain gene expression, and provide support for homing and successful differentiation of infiltrated stem cells [255]. Recently, several studies explored controlled-release plasmid DNA using hydrogels and microspheres [256,257]. These studies have reported that complexation with gelatin can reduce the degradation of DNA from nucleases and may facilitate cellular entry through interaction of positively charged complexes with negatively charged cell membranes [258]. Furthermore, a novel hydro-gel composite of oligo(poly(ethylene glycol) fumarate) (OPF) and cationized gelatin microspheres (CGMS) have been demonstrated to have potential for controlled gene delivery in tissue engineering applications [255].

Most recent studies have demonstrated applications of nanogels composed of am-phiphilic polymers and cationic polyethylenimine for delivery of cytotoxic nucleo-side analogs 5'-triphosphates (NTPs) into cancer cells [259]. Similarly, other studies have demonstrated that nanogels composed of N-isopropylacrylamide (NIPAM) and N-vinylpyrrolidone (VP) cross-linked with N,N'-methylenebisacrylamide (MBA) coated with polysorbate 80 can be used to encapsulate N-hexylcarbamoyl-5-fluorouracil (HCFU) for targeting to the brain [260]. Thus, the nanogel-based delivery systems have opened a new avenue for drug delivery applications.

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