Facile Fabrication of NIR-Responsive Alginate/CMC Hydrogels Derived through IEDDA Click Chemistry for Photothermal-Photodynamic Anti-Tumor Therapy.

Novel chemically cross-linked hydrogels derived from carboxymethyl cellulose (CMC) and alginate (Alg) were prepared through the utilization of the norbornene (Nb)-methyl tetrazine (mTz) click reaction. The hydrogels were designed to generate reactive oxygen species (ROS) from an NIR dye, indocyanine green (ICG), for combined photothermal and photodynamic therapy (PTT/PDT). The cross-linking reaction between Nb and mTz moieties occurred via an inverse electron-demand Diels-Alder chemistry under physiological conditions avoiding the need for a catalyst. The resulting hydrogels exhibited viscoelastic properties (G' ~ 492-270 Pa) and high porosity. The hydrogels were found to be injectable with tunable mechanical characteristics. The ROS production from the ICG-encapsulated hydrogels was confirmed by DPBF assays, indicating a photodynamic effect (with NIR irradiation at 1-2 W for 5-15 min). The temperature of the ICG-loaded hydrogels also increased upon the NIR irradiation to eradicate tumor cells photothermally. In vitro cytocompatibility assessments revealed the non-toxic nature of CMC-Nb and Alg-mTz towards HEK-293 cells. Furthermore, the ICG-loaded hydrogels effectively inhibited the metabolic activity of Hela cells after NIR exposure.

Multi-stimuli responsive hydrogels derived from hyaluronic acid for cancer therapy application.

One of the most promising strategies for the controlled release of therapeutic molecules is stimuli-responsive and biodegradable hydrogels developed from natural polymers. However, current strategies to development stimuli-responsive hydrogels lack precise control over drug release profile and use cytotoxic materials during preparation. To address these issues, multi-stimuli responsive hydrogels derived from hyaluronic acid and diselenide based cross-linker were developed for the controlled release of doxorubicin (DOX). Hydrogels were rapidly formed via an inverse electron demand Diels-Alder click chemistry and encapsulated DOX/indocyanine green (ICG) in their porous networks. The hydrogels showed a rapid release of DOX in acidic (pH 5), reducing (10 mmol DTT), and oxidizing medium (0.5% H2O2), and after NIR irradiation. The in vitro experiments demonstrated that hydrogels were highly cytocompatible and the DOX-loaded hydrogels induced similar anti-tumor effect as compared to that of the free-DOX. Furthermore, DOX + ICG loaded hydrogels increased the antitumor efficacy of DOX after NIR irradiation.

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.

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.

Preparation of Doxorubicin-Loaded Amphiphilic Poly(D,L-Lactide-Co-Glycolide)-b-Poly(N-Acryloylmorpholine) AB2 Miktoarm Star Block Copolymers for Anticancer Drug Delivery.

Owing to their unique topology and physical properties, micelles based on miktoarm amphiphilic star block copolymers play an important role in the biomedical field for drug delivery. Herein, we developed a series of AB2-type poly(D,L-lactide-co-glycolide)-b-poly(N-acryloyl morpholine) (PLGA-b-PNAM2) miktoarm star block copolymers by reversible addition-fragmentation chain-transfer polymerization and ring-opening copolymerization. The resulting miktoarm star polymers were investigated by 1H NMR spectroscopy and gel permeation chromatography. The critical micellar concentration value of the micelles increases with an increase in PNAM block length. As revealed by transmission electron microscopy and dynamic light scattering, the amphiphilic miktoarm star block copolymers can self-assemble to form spherical micellar aggregates in water. The anticancer drug doxorubicin (DOX) was encapsulated by polymeric micelles; the drug-loading efficiency and drug-loading content of the DOX-loaded micelles were 81.7% and 9.1%, respectively. Acidic environments triggered the dissociation of the polymeric micelles, which led to the more release of DOX in pH 6.4 than pH 7.4. The amphiphilic PLGA-b-PNAM2 miktoarm star block copolymers may have broad application as nanocarriers for controlled drug delivery.

Diselenide Core Cross-Linked Micelles of Poly(Ethylene Oxide)-b-Poly(Glycidyl Methacrylate) Prepared through Alkyne-Azide Click Chemistry as a Near-Infrared Controlled Drug Delivery System.

In this article, a drug delivery system with a near-infrared (NIR) light-responsive feature was successfully prepared using a block copolymer poly(ethylene oxide)-b-poly(glycidyl methacrylate)-azide (PEO-b-PGMA-N3) and a cross-linker containing a Se-Se bond through "click" chemistry. Doxorubicin (DOX) was loaded into the core-cross-linked (CCL) micelles of the block copolymer along with indocyanine green (ICG) as a generator of reactive oxygen species (ROS). During NIR light exposure, ROS were generated by ICG and attacked the Se-Se bond of the cross-linker, leading to de-crosslinking of the CCL micelles. After NIR irradiation, the CCL micelles were continuously disrupted, which can be a good indication for effective drug release. Photothermal analysis showed that the temperature elevation during NIR exposure was negligible, thus safe for normal cells. In vitro drug release tests demonstrated that the drug release from diselenide CCL micelles could be controlled by NIR irradiation and affected by the acidity of the environment.