pH-Responsive Poly(Ethylene Glycol)-block-Polylactide Micelles for Tumor-Targeted Drug Delivery

Abstract

A biodegradable micellar drug delivery system with a pH-responsive sheddable PEG shell was developed using an acetal-linked poly(ethylene glycol)-block-polylactide (PEG-a-PLA) copolymer and applied to the tumoral release of paclitaxel (PTX). The micelles with a diameter of ∼100 nm were stable in PBS at pH 7.4, started shedding the shell and aggregating slowly at pH 6.5, and decomposed faster at pH 5.5. PTX-loaded micelles (M-PTX) with a drug loading of 6.9 wt % exhibited pH-triggered PTX release in simulated tumoral acidic environments corresponding to the extracellular and intracellular spaces. In vitro experiments showed that the micelles were noncytotoxic to different cell lines, while M-PTX inhibited the proliferation and promoted the apoptosis of Hela cells. An in vivo study with Hela tumor-bearing mice indicated that M-PTX efficiently inhibited tumor growth. Because of these properties, the PEG-a-PLA micellar system appears to have bright prospects as a tumor-targeting drug carrier.

DePEGylation strategies to increase cancer nanomedicine efficacy

“…* this route does not overcome the "PEG dilemma" and the very limited uptake of PEGylated nanoparticles is a major drawback of these systems. [46][47][48][49] Micelles [50] Hydrazone Liposomes [52][53][54] Micelles [55][56][57][58][59][60][61] Acetal Liposomes [62] Micelles [63][64][65][66][67][68][69] β-thiopropionate Micelles [70] Ortho ester Liposomes [71][72][73] Benzoic-imine Micelles [74][75][76] Reduction Glutathione (GSH) (2-10 mM) Liposomes [93] Polymersomes [94,95] Micelles 133] Graphene Oxide [122][123][124] Mesoporous silica nanoparticles (MSN) [125][126][127][128][129][130][131][132] Magnetic nanoparticles [134] Enzymatic Cathepsin B (peptide consensus sequence)…”

“…45 For this, chemical functionalities stable at physiological pH (pH 7.4) but labile at lower pH are required. The most commonly used acid labile chemical groups are vinyl ethers, [46][47][48][49][50] hydrazones, [51][52][53][54][55][56][57][58][59][60][61] acetals, [62][63][64][65][66][67][68][69] β-thiopropionates, 70 ortho esters [71][72][73] and benzoic imines [74][75][76][77][78][79][80][81][82] . Here accompanied by a significant increase in hemolytic activity suggesting partial dePEGylation was sufficient to endow these particles with the desired function.…”

Self-Assembly of Organic Nanomaterials and Biomaterials: The Bottom-Up Approach for Functional Nanostructures Formation and Advanced Applications

“…Moreover, self-assembly of amphiphilic block copolymers represents a versatile tool for the design of versatile nanocarriers for drug delivery applications. More specifically, the di-and tri-block copolymer of poly(ethylene glycol)/polylactide (PEG/PLA) systems, in the form of both polymer micelles and vesicles (polymersome), are attractive delivery systems since they are biodegradable with a good safety profile and sustained drug delivery [84,85]. The presence of the PEG on the nanocarrier shell prevents the unwanted adsorption of proteins and phagocytes, thereby increasing the period of the blood circulation, while the PLA hydrophobic core can efficiently encapsulate a variety of therapeutic agents [12,80].…”

“…biodegradable with a good safety profile and sustained drug delivery [84,85]. The presence of the PEG on the nanocarrier shell prevents the unwanted adsorption of proteins and phagocytes, thereby increasing the period of the blood circulation, while the PLA hydrophobic core can efficiently encapsulate a variety of therapeutic agents [12,80].…”

Drug Delivery with Polymeric Nanocarriers—Cellular Uptake Mechanisms

“…Monodisperse poly(ethylene glycol)-b-poly(lactide) (PEG-b-PLA) micelles were already produced by Yasugi et al [116] in 1999 with a PDI of <0.1 and are still being investigated as a potential DDS [117].…”