CHEMICAL MODIFICATIONS

Chemical modifications of peptide and protein drugs along with encapsulation in nano/ microparticles may stabilize the molecules from hydrolysis and enzymatic effects.

PEGylation

PEGylation is a chemical modification that involves conjugation of active polyethylene glycol (PEG) to a therapeutic protein/peptide or to a delivery system (nanoparticle). PEGylation offers several advantages such as favorable pharmacokinetics, more stability, and enhanced therapeutic activity [1]. PEGylation of a molecule can cause changes in physicochemical properties such as increase in hydrophilicity, size, and molecular weight, changes in conformation, and steric hindrance of intermolecular interaction [6]. Studies have shown that PEGylation of targeted drug delivery may decrease clearance and enhance delivery of peptide and protein molecules [6,7].

PEGylated poly(lactone-co-b-amino ester) nanoparticles for gene delivery were investigated [8]. Results indicate that diblock copolymer containing PEG—poly with 15% u-pentadecalactone (PDL) (PEG—PPM-15% PDL) micelle particles caused cellular uptake, superior gene transfection efficacy, DNA binding ability, and effective endosomal escape [8]. In vitro antitumor activity was investigated by PEGylating small interference RNA (siRNA) lipoplexes for silencing B-lymphocyte induced maturation protein (BLIMP-1) in lymphoma cells [9]. PEGylation generated stable siRNA lipoplexes of size 300 nm and 80% complexation efficiency [9]. BLIMP-1 protein levels were lower leading to reduction of viability and activation of apoptosis by PEGylated lipoplexes [9]. PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulated bovine serum albumin (BSA), 200 nm in size and with 48.6% entrapment efficiency, were investigated by Li et al. These nanoconstructs extended the half-life of BSA from 13.6 min to 4.5 h relative to non-PEGylated nanoparticles [10]. PEGylated micelles for protein delivery have also been explored. Jiang et al. studied PEGylated albumin-based polyion complex micelles for protein delivery. PEGylated albumin complex micelles were 15—25 nm in size and inhibited growth of MCF-7 [11]. These micelles may be applied in cancer treatment.

PEGylation of microparticles to improve therapeutic applications such as bioassay, degradation, and release kinetics have been studied by several groups. PEGylated microparticles with neuregulin (NRG) growth factor for myocardial infracted hearts were examined by Pascual-Gil et al. [12]. PEGylated PLGA microparticles encapsulating NRG resulted in the reduction ofphagocytosis relative to non-PEGylated microparticles [12]. Controlled release of NRG over 12 weeks was studied. Cardiomyocyte receptors for NRG were activated in animals treated with microparticles loaded with NRG [12]. PEGylated microparticles for microfluidic assay have been also evaluated. PEGylation of magnetic poly (glycidyl methacrylate) microparticles encapsulating BSA was investigated for nonspecific adsorption [13]. Microparticles with 30 kDa PEG produced 45% reduction in nonspecific adsorption of proteins [13]. Moreover, aggregation and adhesion of PEGylated microparticles in microfluidic devices were lower relative to non-PEGylated microparticles [13].

 
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