Boosting Nanomedicine Efficacy with Hyperbaric Oxygen Therapy.

Nanomedicine has been a hot topic in the field of tumor therapy in the past few decades. Because of the enhanced permeability and retention effect (EPR effect), nanomedicine can passively yet selectively accumulate at tumor tissues. As a result, it can improve drug concentration in tumor tissues and reduce drug distribution in normal tissues, thereby contributing to enhanced antitumor effect and reduced adverse effects. However, the therapeutic efficacy of anticancer nanomedicine is not satisfactory in clinical settings. Therefore, how to improve the clinical therapeutic effect of nanomedicine has become an urgent problem. The grand challenges of nanomedicine lie in how to overcome various pathophysiological barriers and simultaneously kill cancer cells effectively in hypoxic tumor microenvironment (TME). To this end, the development of novel stimuli-responsive nanomedicine has become a new research hotspot. While a great deal of progress has been made in this direction and preclinical results report many different kinds of promising multifunctional smart nanomedicine, the design of these intelligent nanomedicines is often too complicated, the requirements for the preparation processes are strict, the cost is high, and the clinical translation is difficult. Thus, it is more practical to find solutions to promote the therapeutic efficacy of commercialized nanomedicines, for example, Doxil®, Oncaspar®, DaunoXome®, Abraxane®, to name a few. Increasing attention has been paid to the combination of modern advanced medical technology and nanomedicine for the treatment of various malignancies. Recently, we found that hyperbaric oxygen (HBO) therapy could enhance Doxil® antitumor efficacy. Inspired by this study, we further carried out researches on the combination of HBO therapy with other nanomedicines for various cancer therapies, and revealed that HBO therapy could significantly boost antitumor efficacy of nanomedicine-mediated photodynamic therapy and photothermal therapy in different kinds of tumors, including hepatocellular carcinoma, breast cancer, and gliomas. Our results implicate that HBO therapy might be a universal strategy to boost therapeutic efficacy of nanomedicine against hypoxic solid malignancies.

Mesoporous polydopamine-based multifunctional nanoparticles for enhanced cancer phototherapy.

Cancer phototherapy has attracted increasing attention for its effectiveness, relatively low side effect, and noninvasiveness. The combination of photothermal therapy (PTT) and photodynamic therapy (PDT) has been shown to exhibit promising prospects in cancer treatment. However, the tumor hypoxia, high level of intracellular glutathione (GSH), and insufficient photosensitizer uptake significantly limit the PDT efficacy. In this work, we combine oxygen supply, GSH depletion, and tumor targeting in one nanoplatform, folate-decorated mesoporous polydopamine nanoparticles (FA-MPPD) co-loaded with new indocyanine green (IR-820) and perfluorooctane (PFO) (IR-820/PFO@FA-MPPD), to overcome the PDT resistance for enhanced cancer PDT/PTT. IR-820/PFO@FA-MPPD exhibit efficient singlet oxygen generation and photothermal effect under 808 nm laser irradiation, GSH-promoted IR-820 release, and efficient cellular uptake, resulting in high intracellular reactive oxygen species (ROS) level under 808 nm laser irradiation and strong photocytotoxicity in vitro. Following intratumoral injection, IR-820/PFO@FA-MPPD can relieve tumor hypoxia sustainably by PFO-mediated oxygen transport and deplete intracellular GSH by the Michael addition reaction, which boost the PDT effect and lead to the most potent antitumor effect upon 808 nm laser irradiation. The multifunctional IR-820/PFO@FA-MPPD developed in this work offer a relatively simple and effective strategy to potentiate PDT for efficient cancer phototherapy.

A novel prodrug and its nanoformulation suppress cancer stem cells by inducing immunogenic cell death and inhibiting indoleamine 2, 3-dioxygenase.

Cancer stem cells (CSCs) present grand challenges for triple-negative breast cancer (TNBC). Conventional chemotherapy drugs, including Camptothecin (CPT), not only cannot eradicate CSCs but also foster a suppressive immune microenvironment for the initiation and proliferation of CSCs. Herein, we report a novel prodrug CPT-SS-NLG919 (CN) and its nanoformulation CN@PLA-HES-FA (CN@PHF), which potently suppress CSCs by regulating CSCs niche in murine TNBC 4T1 tumors. Via inducing immunogenic cell death (ICD) and simultaneous inhibiting indoleamine 2, 3-dioxygenase (IDO), CN and CN@PHF promote DC maturation, decrease Treg cells, mitigate tryptophan consumption, and reduce the amount of IL-6, IL-13, and TGF-ß, converting CSCs niche to a hostile condition for CSCs to live in and eliminating CSCs efficiently, thereby inducing efficient tumor inhibition in 4T1 tumor models. Our work represents a new paradigm of eliminating CSCs by regulating tumor immune microenvironment and suggests that CN and its nanoformulation CN@PHF are promising candidates for the treatment of intractable TNBC.

Hyperbaric Oxygen Boosts PD-1 Antibody Delivery and T Cell Infiltration for Augmented Immune Responses Against Solid Tumors.

Aberrant mechanical properties and immunosuppression are the two key factors that limit the antitumor efficacy of T cell immune checkpoint blockade inhibitors, e.g., programmed cell death-1 antibody (PD-1 Ab), against solid tumors in the clinic. This study leverages hyperbaric oxygen (HBO) for the first time to address these two issues and reports the PD-1-Ab-mediated immune responses against various stroma-rich solid malignancies. The results demonstrate that HBO promoted PD-1 Ab delivery and T cells infiltration into tumor parenchyma by depleting the extracellular matrix's main components, such as collagen and fibronectin. Furthermore, HBO disrupts hypoxia-mediated immunosuppression and helps PD-1 Ab trigger robust cytotoxic T lymphocytes and long-lasting immunological memory to inhibit tumor relapses. Such enhanced immune responses are effective in solid tumors from rodents and the cancer cells from hepatocellular carcinoma patients. The results illustrate that HBO bolsters antitumor efficacy of PD-1 Ab, and the HBO-PD-1 Ab combination is a promising stroma-rich solid tumors' treatment in the clinic.