Ultrasound targeted microbubble destruction-triggered nitric oxide release via nanoscale ultrasound contrast agent for sensitizing chemoimmunotherapy

Abstract

Immunotherapy had demonstrated inspiring effects in tumor treatment, but only a minority of people could benefit owing to the hypoxic and immune-suppressed tumor microenvironment (TME). Therefore, there was an urgent need for a strategy that could relieve hypoxia and increase infiltration of tumor lymphocytes simultaneously. In this study, a novel acidity-responsive nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) was constructed to co-deliver paclitaxel (PTX) and L-arginine (L-Arg) using the homogenization/emulsification method. The L-Arg@PTX nanodroplets with uniform size of about 300 nm and high drug loading efficiency displayed good ultrasound diagnostic imaging capability, improved tumor aggregation and achieved ultrasound-triggered drug release, which could prevent the premature leakage of drugs and thus improve biosafety. More critically, L-Arg@PTX nanodroplets in combination with ultrasound targeted microbubble destruction (UTMD) could increase cellular reactive oxygen species (ROS), which exerted an oxidizing effect that converted L-Arg into nitric oxide (NO), thus alleviating hypoxia, sensitizing chemotherapy and increasing the CD8 + cytotoxic T lymphocytes (CTLs) infiltration. Combined with the chemotherapeutic drug PTX-induced immunogenic cell death (ICD), this promising strategy could enhance immunotherapy synergistically and realize powerful tumor treatment effect. Taken together, L-Arg@PTX nanodroplets was a very hopeful vehicle that integrated drug delivery, diagnostic imaging, and chemoimmunotherapy. Graphical Abstract

Nanomaterials augmented bioeffects of ultrasound in cancer immunotherapy

“…In another study [ 171 ] more skillfully combined SDT, NO gas therapy with chemotherapy, they prepared nanodroplets that co-delivered paclitaxel and L-arginine (L-Arg) by homogenization/emulsification method. The bubbles generated by L-Arg@PTX nanodroplets under ultrasound can greatly promote the release and accumulation of sonosensitizers in deep tissues, and the cavitation effect can reduce the cavitation threshold intensity of SDT.…”

Ultrasound-Based Micro-/Nanosystems for Biomedical Applications

“…Under low-intensity ultrasound, they produce a series of biological effects, thereby mediating drug delivery, gene transfection, tissue barrier opening, immunotherapy, and so on, laying a solid foundation for precision treatment, forming "one-stop precise diagnosis and treatment" model that integrates early diagnosis, targeted therapy, and efficacy evaluation of tumors. 1145 For instance, Li et al 249 reported the application of UTMD technology combined with nanoscale ultrasound contrast agents in the effective controlled release of NO and its sensitized tumor chemotherapy immune combination therapy. In this study, O-carboxymethyl chitosan with exogenous ultrasound-responsiveness and endogenous acidity-responsiveness was used as the shell, and PFH, which can achieve ultrasonic contrast, was used as the core to prepare a nanoscale ultrasound contrast agent (L-Arg@PTX nanodroplets) that combined chemotherapy drugs and NO donors.…”

Amplifying “eat me signal” by immunogenic cell death for potentiating cancer immunotherapy

“…Studies have demonstrated that several chemotherapeutic agents, including doxorubicin, cisplatin, oxaliplatin, and paclitaxel can induce apoptosis in tumor cells as well as elicit ICD via ERS response. 42 Dying tumor cells following specialized chemotherapeutics can trigger ICD to facilitate CALR translocation on the surface, which is considered an "eat me signal" for APCs. In addition, dying tumor cells release ATP and HMGB1 to activate DCs.…”