Degradable Ketal-Based Block Copolymer Nanoparticles for Anticancer Drug Delivery: A Systematic Evaluation

Abstract

Low solubility of potent (anticancer) drugs is a major driving force for the development of noncytotoxic, stimuli-responsive nanocarriers, including systems based on amphiphilic block copolymers. In this regard, we investigated the potential of block copolymers based on 2-hydroxyethyl acrylate (HEA) and the acid-sensitive ketal-containing monomer (2,2-dimethyl-1,3-dioxolane-4-yl)methyl acrylate (DMDMA) to form responsive drug nanocarriers. Block copolymers were successfully synthesized by sequential reversible addition-fragmentation chain transfer (RAFT) polymerization, in which we combined a hydrophilic poly(HEA)x block with a (responsive) hydrophobic poly(HEAm-co-DMDMAn)y copolymer block. The DMDMA content of the hydrophobic block was systematically varied to investigate the influence of polymer design on physicochemical properties and in vitro biological performance. We found that a DMDMA content higher than 11 mol % is required for self-assembly behavior in aqueous medium. All particles showed colloidal stability in PBS at 37 °C for at least 4 days, with sizes ranging from 23 to 338 nm, proportional to the block copolymer DMDMA content. Under acidic conditions, the nanoparticles decomposed into soluble unimers, of which the decomposition rate was inversely proportional to the block copolymer DMDMA content. Flow cytometry and confocal microscopy showed dose-dependent, active in vitro cellular uptake of the particles loaded with hydrophobic octadecyl rhodamine B chloride (R18). The block copolymers showed no intrinsic in vitro cytotoxicity, while loaded with paclitaxel (PTX), a significant decrease in cell viability was observed comparable or better than the two commercial PTX nanoformulations Abraxane and Genexol-PM at equal PTX dose. This systematic approach evaluated and showed the potential of these block copolymers as nanocarriers for hydrophobic drugs.

Cancer-associated fibroblasts as target and tool in cancer therapeutics and diagnostics

“…Paclitaxel (PTX, a microtubule stabilizer causing mitotic arrest) is hydrophobic and water insoluble. The cremophors added to solubilize PTX give serious side effects [32,66]. However, PTX stabilized by albumin (nab-paclitaxel or Abraxane) is soluble and has reduced systemic toxicity and increased efficacy against several cancer types [71].…”

Probing the causes of thermal hysteresis using tunable Nagg micelles with linear and brush-like thermoresponsive coronas

“…The understanding and utilization of stimuli-responsive polymer materials has opened up new avenues in potential applications such as their use as drug delivery vehicles, 1–5 smart surface coatings, 6,7 for detection of specific molecules or ions, 6,8–11 and for enhanced oil recovery 12 to name just a few. These materials respond dramatically to subtle environmental changes such as light, pH, CO 2 , glucose or redox changes.…”

α-TOS-based RAFT block copolymers and their NPs for the treatment of cancer

“…Macromolecular self-assembly represents a spontaneous process that involves the organization of amphiphilic macromolecules in an aqueous environment, forming different supramolecular structures 6, 7 . One interesting example of this variety of supramolecular assemblies is nanoparticles (NPs) that exhibit a core-shell morphology based on the use of amphiphilic polymers with hydrophobic and hydrophilic domains 8–10 .…”