Cisplatin-Induced Formation of Biocompatible and Biodegradable Polypeptide-Based Vesicles for Targeted Anticancer Drug Delivery

Abstract

Novel cisplatin (CDDP)-loaded, polypeptide-based vesicles for the targeted delivery of cisplatin to cancer cells have been prepared. These vesicles were formed from biocompatible and biodegradable maleimide-poly(ethylene oxide)114-b-poly(L-glutamic acid)12 (Mal-PEG114-b-PLG12) block copolymers upon conjugation with the drug itself. CDDP conjugation forms a short, rigid, cross-linked, drug-loaded, hydrophobic block in the copolymer, and subsequently induces self-assembly into hollow vesicle structures with average hydrodynamic diameters (Dh) of ∼ 270 nm. CDDP conjugation is critical to the formation of the vesicles. The reactive maleimide-PEG moieties that form the corona and inner layer of the vesicles were protected via formation of a reversible Diels-Alder (DA) adduct throughout the block copolymer synthesis so as to maintain their integrity. Drug release studies demonstrated a low and sustained drug release profile in systemic conditions (pH = 7.4, [Cl(-)] = 140 mM) with a higher "burst-like" release rate being observed under late endosomal/lysosomal conditions (pH = 5.2, [Cl(-)] = 35 mM). Further, the peripheral maleimide functionalities on the vesicle corona were conjugated to thiol-functionalized folic acid (FA) (via in situ reduction of a novel bis-FA disulfide, FA-SS-FA) to form an active targeting drug delivery system. These targeting vesicles exhibited significantly higher cellular binding/uptake into and dose-dependent cytotoxicity toward cancer cells (HeLa) compared to noncancerous cells (NIH-3T3), which show high and low folic acid receptor (FR) expression, respectively. This work thus demonstrates a novel approach to polypeptide-based vesicle assembly and a promising strategy for targeted, effective CDDP anticancer drug delivery.

Responsive hybrid (poly)peptide–polymer conjugates

“…Diblocks consisting of PEG and poly(L-glutamic acid) (PLGA) have been used for micelle formation for delivery of platinum drugs, 76–80 and conjugation of cisplatin to the carboxylic acid side chain results in subsequent vesicle formation. 81 Incorporation of a poly(L-leucine) into a PEG-PLeu-PLGA triblock allowed for controlled release of a loaded drug due to the pH-responsive conformational change of the PLGA block. In another example, Wooley and co-workers have also used NCA ROPs to develop di- and triblock conjugates consisting of oligopeptides whose secondary structure can drive the formation of gels.…”

Microwave-assisted synthesis of thermo- and pH-responsive antitumor drug carrier through reversible addition–fragmentation chain transfer polymerization

“…The FTIR spectra verified the conjugation between the polymer and cisplatin, as indicated in Figure 11. The spectra also exhibited two pronounced peaks at 3292 and 1385 cm -1 , revealing the absorptions of N-H stretching from cisplatin ligands (Pt-NH 2 ), and the chelation of the COO-Pt stretch, respectively [47,48]. In addition, a reduction in absorbance of the carbonyl (C=O) stretch of COOH at 1704 cm -1 relative to the amide C=O band at 1633 cm -1 (the difference between relative intensity in (a) and (b) in Figure 11) is consistent with the prediction that some of the -COOH groups would react with the Pt atoms in a ligand exchange reaction [49].…”

Multifunctional platinum‐based nanoparticles for biomedical applications

“…Qiao et al designed a cisplatin‐loaded, polypeptide‐based vesicles functionalized with folic acid for targeted cisplatin delivery. These targeting vesicles showed significantly higher cellular uptake and dose‐dependent cytotoxicity toward HeLa cells (high FR expression) compared to NIH‐3 T3 cells (low FR expression) …”