Fabrication of Acidic pH-Cleavable Polymer for Anticancer Drug Delivery Using a Dual Functional Monomer

Abstract

The preparation of tumor acidic pH-cleavable polymers generally requires tedious postpolymerization modifications, leading to batch-to-batch variation and scale-up complexity. To develop a facile and universal strategy, we reported in this study design and successful synthesis of a dual functional monomer, a-OEGMA that bridges a methacrylate structure and oligo(ethylene glycol) (OEG) units via an acidic pH-cleavable acetal link. Therefore, a-OEGMA integrates (i) the merits of commercially available oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) monomer, i.e., hydrophilicity for extracellular stabilization of particulates and a polymerizable methacrylate for adopting controlled living radical polymerization (CLRP), and (ii) an acidic pH-cleavable acetal link for efficiently intracellular destabilization of polymeric carriers. To demonstrate the advantages of a-OEGMA ( M = 500 g/mol) relative to the commercially available OEGMA ( M = 300 g/mol) for drug delivery applications, we prepared both acidic pH-cleavable poly(ε-caprolactone)- b-poly( a-OEGMA) (PCL- b-P( a-OEGMA)) and pH-insensitive analogues of PCL- b-P(OEGMA) with an almost identical molecular weight (MW) of approximately 5.0 kDa for the hydrophilic blocks by a combination of ring-opening polymerization (ROP) of ε-CL and subsequent atom transfer radical polymerization (ATRP) of a-OEGMA or OEGMA. The pH-responsive micelles self-assembled from PCL- b-P( a-OEGMA) showed sufficient salt stability, but efficient acidic pH-triggered aggregation that was confirmed by the DLS and TEM measurements as well as further characterizations of the products after degradation. In vitro drug release study revealed significantly promoted drug release at pH 5.0 relative to the release profile recorded at pH 7.4 due to the loss of colloidal stability and formation of micelle aggregates. The delivery efficacy evaluated by flow cytometry analyses and an in vitro cytotoxicity study in A549 cells further corroborated greater cellular uptake and cytotoxicity of Dox-loaded pH-sensitive micelles of PCL- b-P( a-OEGMA) relative to the pH-insensitive analogues of PCL- b-P(OEGMA). This study therefore presents a facile and robust means toward tumor acidic pH-responsive polymers as well as provides one solution to the trade-off between extracellular stability and intracellular high therapeutic efficacy of drug delivery systems using a novel monomer of a-OEGMA with dual functionalities.

Triple Functional AB2 Unit-Modulated Facile Preparation of Bioreducible Hyperbranched Copolymers

“…4−7 The HPs can be used as a promising alternative to dendrimers for catalysis, 8 material modification, 9 bioimaging, 10 drug delivery, 11 chemistry separation, 12 biosensing, 13 and dispersion/solubilization. 14 Generally, the facile preparation of HPs has been advanced tremendously by two reported mainstream strategies including (1) a controlled living radical polymerization mediated by a dual or multifunctional agent that usually contains variable structures of polymerizable double bonds, initiators, 15−21 chain transfer functional groups, 22,23 or crosslinkers 24−27 and (2) a self-stepwise polymerization by the use of a highly reactive AB x unit. 28−30 One notable example of the first approach is Wei's all-in-one chain transfer agent (CTA) for a one-pot preparation of a dual-responsive hyperbranched polymeric prodrug via a self-condensing vinyl polymerization (SCVP) process.…”

Advanced Nano-Carriers for Anti-Tumor Drug Loading

“…The pH value of normal tissue is about 7.4, while the pH value of tumor extracellular microenvironment is about 6.5~7.2 ( 66 ). Researchers have developed pH-responsive drug carrier systems by introducing alkaline polymers containing multiple amino groups into polymers, or acetals, orthoesters, hydrazine bonds that can be broken in acidic environments ( 67 – 69 ). This carrier systems were often used to control drug release in specific organs (such as the gastrointestinal tract or vagina) or organelles (such as nucleosomes or lysosomes) and trigger drug release when microenvironment changes are associated with pathological conditions ( 70 ).…”

From gas release to foam synthesis, the second breath of blowing agents

“…Polymer containing acetal links shouldn't be use with this CBA system because acidic condition could cleave acetals. 100 . When the acid is mixed in the mold with the solid magnesium it will react in order to blow the foam.…”