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-co-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)-block-poly(ε-caprolactone) (PEG-b-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-b-PCL nanoparticles loading polymer prodrugs (PPEMA-b-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-b-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-b-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.

Near-infrared light-triggered drug release nanogels for combined photothermal-chemotherapy of cancer.

Near-infrared (NIR) light-triggered drug release systems are promising for drug delivery applications in view of the advantages of NIR light, which include high tissue penetration and low damage. In this report, we developed nanogels (NGs) by supramolecular self-assembly from adamantine (AD)-conjugated copolymer, poly[poly(ethylene glycol)monomethyl ether metharcylate]-co-poly(N-(2-hydroxypropyl)methacrylamide)-co-poly(N-adamantan-1-yl-2-methacrylamide) (PPEGMA-co-PHPMA-co-PADMA), and ß-cyclodextrin (ß-CD)-functionalized poly(amidoamine) (PAMAM) dendrimer based on the host-guest interaction of the AD and ß-CD moieties, and they were used to encapsulate indocyanine green (ICG) and doxorubicin (DOX) for combined photothermal-chemotherapy. NGs simultaneously loading ICG and DOX (DINGs) showed significant photothermal effects and stimuli-triggered drug release under NIR laser irradiation by the photothermal-induced relaxation or dissociation of the NGs. In vitro cytotoxicity evaluation of DINGs under NIR irradiation demonstrated the synergistic effects of hyperthermia, photothermal-triggered drug release, and chemotherapy. In vivo investigation revealed their high accumulation in tumor tissue and significant tumor growth suppression under NIR irradiation. These NIR light-triggered drug release NGs represent efficient and promising anticancer drug vectors for the combined photothermal-chemotherapy of cancer to maximize therapeutic efficacy and minimize side effects.