Synthesis and Characterization of Peptidomimetic Self-Assembled Biodegradable Nanoparticles
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Synthesis and Characterization of Peptidomimetic Self-Assembled Biodegradable Nanoparticles Ángel E. Mercado-Pagán and Esmaiel Jabbari Biomimetic Materials and Tissue Engineering Laboratories Department of Chemical Engineering University of South Carolina, Columbia, SC 29208, U.S.A. ABSTRACT Nanoparticles (NPs) are being used extensively for tumor drug delivery. These devices offer the advantage of their size, protection of the encapsulated species, and biodegradability to prevent accumulation in the interstitium. Our laboratory has synthesized polylactide fumarate (PLAF, PLGF) macromers capable of self-assembling into biodegradable and biocompatible NPs with average particle size of 280 nm. To assess the possibility of further decreasing the particle size and distribution of PLGF NPs, the polymers were conjugated with the peptide sequence Cys-Val-Val-Val-Val-Val-Val-Lys-Lys (CV6K2), which is known to self-assemble in aqueous solution into vesicles of about 50-60 nm in size. The results indicate that the PLGF-CV6K2 conjugates are capable of self-assembling into NPs of 100 nm in diameter. The NPs are proposed as having a bilayer structure, with peptide chains facing the aqueous environment and the polymer chains compacted in an internal hydrophobic layer. Degradation kinetics and release profiles show that the NPs could effectively retain and release Paclitaxel up to 30 days until completely degraded. The NPs act as reservoirs for sustained release of the active agent by diffusion and degradation of the matrix when taken up by tumor cells. INTRODUCTION NPs are being considered for their applications in targeted drug delivery to tumor tissue. Tumor tissue has increased permeability (EPR effect) [1-3], which enables particles of less than 200 nm in size to be selectively taken up by tumor vasculature [4, 5]. Surface-modified NPs have the potential to increase the effectiveness of targeted delivery by means of introducing specific ligands that can bind with high specificity to receptors on the cell surface. It is desired that these nano-carriers degrade by biochemical pathways in the organism, to prevent accumulation in the interstitium, and prevent the loss of bioactivity of the agent to be delivered [6, 7]. Our research group has recently synthesized biodegradable NPs from poly(actide-co-glycolide fumarate) (PLGF) macromer for targeted delivery of bioactive agents [8]. It has been demonstrated that the peptide sequence Cys-Val-Val-Val-Val-Val-Val-Lys-Lys (CV6K2) self assembles in aqueous solution into NPs [9]. We hypothesized that the addition of CV6K2 sequence to PLGF macromer would facilitate assembly of the macromer to NPs. The main objectives of the present work is to synthesize PLAF and PLGF macromers conjugated to the CV6K2 sequence, evaluate their selfassembly properties, and characterize them in terms of their morphology, size, degradation properties, release characteristics, and cell uptake. EXPERIMENTAL METHODS PLAF and PLGF synthesis: The low molecular weight poly(lactic acid) (PLA) and poly(l
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