Thermo- and pH-dual responsive polymeric micelles with upper critical solution temperature behavior for photoacoustic imaging-guided synergistic chemo-photothermal therapy against subcutaneous and metastatic breast tumors

Abstract

Chemo-photothermal therapy shows great potential for inhibiting tumor growth. However, achieving maximal chemo-photothermal synergistic efficacy is challenging because of the low efficiency of controllable chemo-drug release in response to external or internal triggers. Thus, a nano-delivery system that could effectively achieve photothermal therapy and dual stimuli-responsive (heat and pH) drug release to inhibit both primary breast tumor growth and metastases is required.Methods: Herein, a thermo- and pH-responsive polymer (mPEG-PAAV) with an upper critical solution temperature (UCST) was synthesized to fabricate a DOX- and IR780-loaded micellar system. After systematic studies of the photothermal performance and controllable drug release of mPEG-PAAV micelles/IR780+DOX under NIR irradiation at different pH values, their chemo-photothermal synergetic therapy efficacies were also estimated both in in vitro and in vivo.Results: Because of the photothermal conversion of mPEG-PAAV micelle/IR780+DOX (~200 nm, 3.82 mV), high local temperature could be induced at the tumor site under NIR laser irradiation. This hyperthermia not only produced an enhanced tumor necrosis, but also broke down the micelles under the decreased pH environment, resulting in rapid DOX release and enhanced intracellular drug accumulation after NIR laser irradiation. In addition, photoacoustic imaging (PAI) of mPEG-PAAV/IR780+DOX micelle was adopted to monitor the morphology and micro-vascular distribution of the tumor tissue, which could also guide the chemo-photothermal therapy. Most importantly, the systemic administration of mPEG-PAAV micelles/IR780+DOX combined with NIR laser irradiation could simultaneously eliminate the 4T1 breast tumor and thoroughly suppress lung metastasis without any obvious adverse effects.Conclusion: Herein, a pH- and thermo-dual responsive UCST micelle system was developed for delivering IR780 and DOX, which could achieve NIR laser-controlled drug release and PA imaging guidance for chemo-photothermal synergistic therapy of both primary breast tumors and their metastases.

Prototypic Heptamethine Cyanine Incorporating Nanomaterials for Cancer Phototheragnostic

“…Nanoformulations incorporating IR780 and other therapeutic agents can also be prepared for cancer combinatorial phototherapy (Table ) . In this regard, Yang et al prepared PEGylated micelles incorporating IR780 and doxorubicin (DOX) for application in cancer chemo‐PTT . These micelles displayed a pH‐ and thermo‐responsiveness, presenting an increased release of the loaded cargo when placed in solutions with an acidic character (i.e., with a pH similar to that exhibited by the tumor microenvironment) and/or upon NIR laser irradiation.…”

“…mPEG‐PAAV micelles/IR780+DOX: PEGylated micelles incorporating IR780 and DOX. Reproduced with permission . Copyright 2018, Ivyspring International Publishers.…”

Organic Nanocarriers for Delivery and Targeting of Therapeutic Agents for Cancer Treatment

“…Tian and coworkers recently reported a pH‐ and thermosensitive poly(ethylene glycol)‐ b ‐poly(acrylamide‐ co ‐acrylonitrile‐ co ‐vinylimidazole) copolymer (mPEG‐PAAV) (Figure 11D) that forms a micellar system that effectively delivers IR780 and DOX to treat metastatic breast cancer. IR780‐ and DOX‐loaded mPEG‐PAAV micelles in combination with NIR laser irradiation remarkably improve the intracellular accumulation of DOX and synergistically resulted in the complete elimination of 4T1 breast tumor and suppress lung metastasis of breast cancer without any adverse effects …”

Bioresponsive Nanomedicine: The Next Step of Deadliest Cancers' Theranostics

“…Meanwhile, several temperature-responsive nanomedicines were also developed for prostate and breast carcinoma therapy (Wadajkar et al, 2013;Yang et al, 2018). These nano-composites are sensitive to the change of temperature (40-43 • ) and will release the cargos at lower or upper critical solution temperature, eventually triggering the anti-cancer effects via chemotherapy or combined therapy.…”