Paclitaxel-Loaded Poly(γ-glutamic acid)-poly(lactide) Nanoparticles as a Targeted Drug Delivery System against Cultured HepG2 Cells

Abstract

The study was to develop paclitaxel-loaded formulations using a novel type of self-assembled nanoparticles that was composed of block copolymers synthesized from poly(gamma-glutamic acid) and poly(lactide) via a simple coupling reaction. The nanoparticles (the NPs) were prepared with various feed weight ratios of paclitaxel to block copolymer (the P/BC ratio). The morphology of all prepared nanoparticles was spherical and the surfaces were smooth. Increasing the P/BC ratio significantly increased the drug loading content of the prepared nanoparticles, but remarkably reduced the drug loading efficiency. The release rate of paclitaxel from the NPs decreased significantly as the P/BC ratio increased. For the potential of targeting liver cancer cells, galactosamine was further conjugated on the prepared nanoparticles (the Gal-NPs) as a targeting moiety. It was found that the activity in inhibiting the growth of HepG2 cells (a liver cancer cell line) by the Gal-NPs was comparable to that of a clinically available paclitaxel formulation, while the NPs displayed a significantly less activity. This may be attributed to the fact that the Gal-NPs had a specific interaction with HepG2 cells via ligand-receptor recognition. Cells treated with distinct paclitaxel formulations resulted in arrest in the G2/M phase. The arrest of cells in the G2/M phase was highly suggestive of interference by paclitaxel with spindle formation and was consistent with the morphological findings presented herein. In conclusion, the active targeting nature of the Gal-NPs prepared in the study may be used as a potential drug delivery system for the targeted delivery to liver cancers.

Heparin–Paclitaxel Conjugates Using Mixed Anhydride as Intermediate: Synthesis, Influence of Polymer Structure on Drug Release, Anticoagulant Activity and In Vitro Efficiency

“…Previous attempts have been largely limited to design of small molecule paclitaxel derivatives, such as ester paclitaxel derivatives and phosphate paclitaxel derivatives, etc (2)(3)(4)(5). In recent years, use of macromolecules for the targeted delivery of anticancer agents has generated considerable interest regarding enhancing therapeutic efficacy and reducing systemic side effects, and some satisfactory results have been obtained (6)(7)(8)(9). Apparently, it would have been desirable to develop drug delivery systems which would be more soluble than paclitaxel, but which, upon hydrolysis under physiological conditions, would exhibit the same or similar level of antitumor activity as free paclitaxel.…”

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

“…In addition, some research studies indicated that only a small amount of NPs without galactosamine was internalized into hepatoma cells, whereas the galactosamine-modified NPs lead to high targeting to hepatic tumor and facilitate their cellular uptake. 73,74 Hence, lactose and galactosamine are also potential ligands to ASGPR. To develop galactosylated polymer for drug and gene delivery to hepatoma cells and hepatocytes, Narain's group synthesized 2-lactobionamidoethyl methacrylamide including Gal residues, 75,76 which could be used in composing copolymer through reversible addition-fragmentation chain transfer polymerization technique.…”

Amphiphilic poly(amino acid) based micelles applied to drug delivery: The in vitro and in vivo challenges and the corresponding potential strategies

“…Numbers of hydrophobic groups or PEG-b-PLL pDNA Electrostatic interactions A D h of ca. 100 nm, a low absolute ζ-potential value and excellent colloidal stability [42] ε-PLL-DDSA-SA BSA; lysozyme Electrostatic interactions EE reached almost 100% for BSA and 90% for lysozyme [28] ε-PLL-g-OSA Curcuminoids Hydrophobic interaction DL of 5.3%; ε-PLL-g-OSA micelles increased solubility of curcuminoids in water by 5000 folds [84] γ-PGlu-b-PLLA PTX Hydrophobic interaction DL of 6.1%; as feed weight ration of PTX to copolymer, DL of PTX-loaded micelle increased [85] γ-PGlu-g-L-PAE ODN-protamine polyplex Electrostatic interactions EE of 80%; the amount of ODN in the micelles and the EE were increased as the ratio of N/P increased [86] PEG-(PCL-b-γ-PGlu) DOX Electrostatic; hydrophobic interaction DL of 12.14% and EE of 97.22%; γ-PGlu block exhibited shrinking and aggregation at low pH which led to a slow drug release [87] polymeric segment have been exploited to modify its α-carboxylic groups or terminal amino group, synthesizing amphiphilic grafted copolymer or block copolymer [23]. These hydrophobic segments included poly(L-lactide) or poly(D-lactide), cholesterol [24], and Lphenylalanine ethylester (L-PAE) [25].…”