pH- and photothermal-driven multistage delivery nanoplatform for overcoming cancer drug resistance.

Reversing multidrug resistance (MDR) remains a big challenge in cancer therapy. Combining the hyperthermia and chemotherapy is a promising strategy for efficient cancer treatment with MDR reversal. Gold nanocages (GNCs) are an ideal photothermal (PTT)-chemotherapy integration platform due to their good photothermal conversion efficiency and the unique hollow interiors. However, insufficient tumor cell internalization and in vivo premature drug leakage restrict the anticancer activity of GNCs-based drug delivery systems. Methods: pH low insertion peptide (pHLIP)- and thermoresponsive poly(di(ethylene glycol) methyl ether methacrylate-co-oligo(ethylene glycol) methyl ether methacrylate) polymer-conjugated GNCs were rationally constructed to load anticancer drug doxorubicin (DOX@pPGNCs). Tumor acidic environment-responsive tumor cell internalization, and near-infrared (NIR) laser-induced tumor accumulation, penetration and on-demand drug release were systematically examined. Results: DOX@pPGNCs display good photothermal efficacy and thermoresponsive property. NIR laser irradiations at the tumor site significantly enhance tumor accumulation and penetration. Once DOX@pPGNCs reach the tumor site, the conformational transformation of pHLIP at the acidic tumor microenvironment contributes to the enhanced cellular internalization. Furthermore, NIR laser-triggered photothermal effects induce the shrinkage of thermoresponsive polymer, resulting in the opening of the pores of GNCs and a rapid intracellular DOX release to the nuclei. DOX@pPGNCs exhibit synergistic antitumor effect with MDR reversal in vitro and in vivo. Conclusion: DOX@pPGNCs present strong potential to overcome MDR in cancer.

A Biomimetic Gold Nanocages-Based Nanoplatform for Efficient Tumor Ablation and Reduced Inflammation.

Gold nanocages (AuNCs), with high photothermal conversion efficiency and unique hollow interiors, have become a promising nanoplatform for synergistic phototheraml therapy (PTT)-chemotherapy. However, the insufficient tumor targeting, in vivo premature drug leakage and low drug loading efficiency responsible for the spatial-temporal un-synchronization of PTT-chemotherapy, as well as inflammatory response might compromise the anticancer treatment of AuNCs-based drug delivery systems. Methods: Cancer cell membrane (CCM)-coated AuNCs were developed to load anticancer drug doxorubicin (DOX@CAuNCs) by transmembrane ammonium sulfate gradient method. In vitro and in vivo analysis, including characterization, macrophage phagocytosis and tumor targeting capacity, near-infrared (NIR) laser-induced drug release, antitumor efficacy and inflammation response were systematically performed. Results: DOX@CAuNCs showed a high DOX loading capacity and on-demand NIR laser-triggered DOX release compared with CAuNCs passively loading DOX by electrostatic adsorption, a commonly used method to load drug to AuNCs. Meanwhile, in view of the properties of CCM coated on AuNCs, DOX@CAuNCs exhibited decreased macrophage phagocytosis, prolonged blood circulation and enhanced internalization by cancer cells, generating preferable tumor targeting ability. With these integrated advantages, DOX@CAuNCs demonstrated highly efficient and precise spatial-temporal synchronization of PTT-chemotherapy, achieving complete tumor ablation with no obvious side effects. Besides, coating with CCM significantly alleviated AuNCs-induced inflammatory response. Conclusion: This biomimetic AuNCs-based platform might be a prospective drug delivery system for precision PTT and chemotherapy, acquiring desired cancer treatment efficacy and low inflammatory response.

Precise synchronization of hyperthermia-chemotherapy: photothermally induced on-demand release from injectable hydrogels of gold nanocages.

Though a therapeutic sequence plays a key role in tumor therapy, little attention has been paid to its influence on multimodal combined therapy. Herein, we developed gold nanocages (GNC@PNA-hls) decorated with two kinds of temperature sensitive p(N-isopropyl-acrylamide-acrylic acid) copolymers (PNA-hs and PNA-ls) for precise antitumor coordination of thermo-chemotherapy. Doxorubicin-loaded GNC@PNA-hls (Dox-GNC@PNA-hls) showed a steady photothermally induced on-demand release under multiple near-infrared (NIR) irradiations. In vitro evaluations indicated that concurrent thermo-chemotherapy treatments (Dox - L) showed the best antitumor effect, compared with the sequence of either doxorubicin treatment followed by NIR radiation (Dox + L) or NIR radiation followed by doxorubicin treatment (L + Dox). The in vivo antitumor efficacy also indicated that the tumor volume was totally suppressed (ca. 0.14 cm3) by the treatment of Dox-GNC@PNA-hls with NIR radiation for 14 days. These results indicated that Dox-GNC@PNA-hls could achieve precise synchronization between hyperthermia and chemotherapy, and effectively enhance their antitumor efficacy.