Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization and Triggered Drug Release

Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles is frequently subjected to low drug loading efficiency (DLE) and loading content (DLC), as well as lower micellar stability and uncontrollable drug release. In this report, we prepare the copolymer prodrugs (PPEMA-<i>co</i>-PCPTM) via reversible addition–fragmentation chain transfer (RAFT) polymerization of 2-(piperidin-1-yl)­ethyl methacrylate (PEMA) and reduction-responsive CPT monomer (CPTM), which were quantitatively encapsulated into poly­(ethylene glycol)-<i>block</i>-poly­(ε-caprolactone) (PEG-<i>b</i>-PCL) micelles. The polymer prodrug-loaded nanoparticles showed high stability for a long time in aqueous solution or blood serum and even maintain similar size after a lyophilization–dissolution cycle. The tumoral pH (∼6.8)-responsive properties of PPEMA segments endow the micellar cores with triggered transition from neutral to positively charged and swellable properties. The PEG-<i>b</i>-PCL nanoparticles loading polymer prodrugs (PPEMA-<i>b</i>-PCPTM) eliminated burst drug release. Simultaneously, CPT drug release can be triggered by reductive agents and solution pH. At pH 6.8, efficient cellular internalization was achieved due to positively charged cores of the nanoparticles. As compared with nanoparticles loading PCPTM, higher cytotoxicity was observed by the nanoparticles loading PPEMA-<i>b</i>-PCPTM at pH 6.8. Further multicellular tumor spheroid (MCTs) penetration and growth suppression studies demonstrated that high-efficiency penetration capability and significant size shrinkage of MCTs were achieved after treatment by PPEMA-<i>b</i>-PCPTM-loaded nanoparticles at pH 6.8. Therefore, the responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the nanoparticles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability