Macrophage-mediated tumor homing of hyaluronic acid nanogels loaded with polypyrrole and anticancer drug for targeted combinational photothermo-chemotherapy.

Rationale: Development of nanosystems that can be integrated with macrophages (MAs), an emerging carrier system, for effective tumor therapy remains to be challenging. We report here the development of MAs specifically loaded with hyaluronic acid (HA) nanogels (NGs) encapsulated with a photothermal agent of polypyrrole (PPy) and anticancer drug doxorubicin (DOX) (HA/DOX@PPy NGs) for tumor homing and combination photothermo-chemotherapy. Methods: Cystamine dihydrochloride-crosslinked HA NGs were first prepared through a double emulsification method, then loaded with PPy via an in-situ oxidization polymerization and physically encapsulated with DOX. The created HA/DOX@PPy NGs were well characterized and subjected to be endocytosed by MAs (MAs-NGs). The MAs-mediated tumor-homing property, phenotype changes and photothermal performance of MAs-NGs were investigated in vitro, and a subcutaneous tumor model was also established to confirm their targeting capability and enhanced antitumor therapy effect in vivo. Results: The generated hybrid NGs possess a size around 77 nm and good colloidal stability, and can be specifically endocytosed by MAs without appreciably affecting their normal biofunctionalities. In particular, NG-loaded MAs display excellent in-vitro cancer cell and in-vivo tumor homing property. Systemic administration of the MAs-NGs leads to the significant inhibition of a subcutaneous tumor model through combination photothermo-chemotherapy under laser irradiation. Conclusions: The developed hybrid HA-based NG nanosystem incorporated with PPy and DOX fully integrates the coordination and heating property of PPy to regulate the optimized DOX release in the tumor region with the assistance of MA-mediated tumor homing, providing a promising cell therapy strategy for enhanced antitumor therapy.

Injectable in Situ Forming Hydrogels of Thermosensitive Polypyrrole Nanoplatforms for Precisely Synergistic Photothermo-Chemotherapy.

The combination of photothermal therapy (PTT) with chemotherapy has great potential to maximize the synergistic effect of thermo-induced chemosensitization and improve treatment performance. To achieve high drug-loading capacity as well as precise synchronization between the controllable release of chemotherapeutics and the duration of near-infrared PTT, in this work, a facile one-step method was first developed to fabricate a novel injectable in situ forming photothermal modulated hydrogel drug delivery platform (D-PPy@PNAs), in which a PNIPAM-based temperature-sensitive acidic triblock polymer [poly(acrylic acid-b-N-isopropylamide-b-acrylic acid (PNA)] was utilized as the stabilizing agent in the polymerization of polypyrrole (PPy). The in situ forming hydrogels showed a sensitive temperature-responsive sol-gel phase-transition behavior, as well as an excellent photothermal property. The strong interaction of ionic bonds together with π-π stacking interactions resulted in high doxorubicin (DOX) loading capacity and controlled/sustained drug release behavior. In addition, D-PPy@PNAs also displayed enhanced cellular uptake and promoted intratumoral penetration of DOX upon NIR laser irradiation. The synergistic photothermal therapy-chemotherapy of D-PPy@PNA hydrogels greatly improved the antitumor efficacy in vivo. Therefore, thermosensitive polypyrrole-based D-PPy@PNA hydrogels may be powerful drug delivery nanoplatforms for precisely synergistic photothermo-chemotherapy of tumors.