Near-Infrared Light-Responsive Shell-Crosslinked Micelles of Poly(d,l-lactide)-b-poly((furfuryl methacrylate)-co-(N-acryloylmorpholine)) Prepared by Diels–Alder Reaction for the Triggered Release of Doxorubicin

Abstract

In the present study, we developed near-infrared (NIR)-responsive shell-crosslinked (SCL) micelles using the Diels–Alder (DA) click reaction between an amphiphilic copolymer poly(d,l-lactide)20-b-poly((furfuryl methacrylate)10-co-(N-acryloylmorpholine)78) (PLA20-b-P(FMA10-co-NAM78)) and a diselenide-containing crosslinker, bis(maleimidoethyl) 3,3′-diselanediyldipropionoate (BMEDSeDP). The PLA20-b-P(FMA10-co-NAM78) copolymer was synthesized by RAFT polymerization of FMA and NAM using a PLA20-macro-chain transfer agent (PLA20-CTA). The DA reaction between BMEDSeDP and the furfuryl moieties in the copolymeric micelles in water resulted in the formation of SCL micelles. The SCL micelles were analyzed by 1H-NMR, FE-SEM, and DLS. An anticancer drug, doxorubicin (DOX), and an NIR sensitizer, indocyanine green (ICG), were effectively incorporated into the SCL micelles during the crosslinking reaction. The DOX/ICG-loaded SCL micelles showed pH- and NIR-responsive drug release, where burst release was observed under NIR laser irradiation. The in vitro cytotoxicity analysis demonstrated that the SCL was not cytotoxic against normal HFF-1 cells, while DOX/ICG-loaded SCL micelles exhibited significant antitumor activity toward HeLa cells. Thus, the SCL micelles of PLA20-b-P(FMA10-co-NAM78) can be used as a potential delivery vehicle for the controlled drug release in cancer therapy.

Peptide-Conjugated Micelles Make Effective Mimics of the TRAIL Protein for Driving Apoptosis in Colon Cancer

“…These polymers were composed of a hydrophilic block of poly N-(2hydroxypropyl)methacrylamide (HPMA), which is known for great biocompatibility and low toxicity, 47 and a hydrophobic block of MMA that was copolymerized with a small portion (20%) of FMA for providing cross-linking reaction sites. 48 All polymerizations were well controlled as evidenced by the clean GPC peak shifts and low dispersities (Đ < 1.2) (ESI, Table S1 and Figure S3). The removal of TMS groups was confirmed from the full disappearance of the methyl protons at δ = 0.18 ppm by 1 H NMR (ESI, Figure S4), yielding PHPMA 23 -b-P(MMA 0.78 -co-FMA 0.22 ) 33 .…”

“… The amphiphilic diblock copolymer was synthesized from the above RAFT agent via two steps of RAFT polymerization followed by the TMS deprotection with tetrabutylammonium fluoride (TBAF) (Figure A, ESI, Figure S2). These polymers were composed of a hydrophilic block of poly N -(2-hydroxypropyl)­methacrylamide (HPMA), which is known for great biocompatibility and low toxicity, and a hydrophobic block of MMA that was copolymerized with a small portion (20%) of FMA for providing cross-linking reaction sites . All polymerizations were well controlled as evidenced by the clean GPC peak shifts and low dispersities ( Đ < 1.2) (ESI, Table S1 and Figure S3).…”

RAFT-Based Polymers for Click Reactions

“…This choice is conditioned by the high versatility of RAFT-based polymers from the standpoint of modification opportunities for both chain-end groups and by low sensitivity of the RAFT process to the chemical nature of the functional groups. The interest to the combination of RAFT polymerization and click chemistry is still growing and new publications appear almost every week [ 229 , 230 , 231 , 232 , 233 ].…”

Review of NIR-responsive ‘‘Smart’’ carriers for photothermal chemotherapy

“…Lim and colleagues conducted the synthesis of NIR-I-responsive micelles through the addition–fragmentation chain-transfer (RAFT) copolymerization. 111 They synthesized an amphiphilic copolymer comprised of three distinct monomers, i.e. , d , l -lactide (LA), N -acryloylmorpholine (NAM), and furfuryl methacrylate (FMA).…”