Tumor Microenvironment-triggered Nanosystems as dual-relief Tumor Hypoxia Immunomodulators for enhanced Phototherapy

Abstract

Photodynamic therapy (PDT) is a promising strategy in cancer treatment that utilizes photosensitizers (PSs) to produce reactive oxygen species (ROS) and eliminate cancer cells under specific wavelength light irradiation. However, special tumor environments, such as those with overexpression of glutathione (GSH), which will consume PDT-mediated ROS, as well as hypoxia in the tumor microenvironment (TME) could lead to ineffective treatment. Moreover, PDT is highly light-dependent and therefore can be hindered in deep tumor cells where light cannot easily penetrate. To solve these problems, we designed oxygen-dual-generating nanosystems MnO 2 @Chitosan-CyI (MCC) for enhanced phototherapy. Methods : The TME-sensitive nanosystems MCC were easily prepared through the self-assembly of iodinated indocyanine green (ICG) derivative CyI and chitosan, after which the MnO 2 nanoparticles were formed as a shell by electrostatic interaction and Mn-N coordinate bonding. Results : When subjected to NIR irradiation, MCC offered enhanced ROS production and heat generation. Furthermore, once endocytosed, MnO 2 could not only decrease the level of GSH but also serve as a highly efficient in situ oxygen generator. Meanwhile, heat generation-induced temperature increase accelerated in vivo blood flow, which effectively relieved the environmental tumor hypoxia. Furthermore, enhanced PDT triggered an acute immune response, leading to NIR-guided, synergistic PDT/photothermal/immunotherapy capable of eliminating tumors and reducing tumor metastasis. Conclusion: The proposed novel nanosystems represent an important advance in altering TME for improved clinical PDT efficacy, as well as their potential as effective theranostic agents in cancer treatment.

An innovative NRF2 nano-modulator induces lung cancer ferroptosis and elicits an immunostimulatory tumor microenvironment

“…However, substantial benefit of immunotherapy is observed only for a limited fraction of cancer patients 14 - 16 . Recently, several NPs have been reported to elicit tumor microenvironment modulation, such as the macrophage reprogramming by manganese dioxide NPs 17 or by magnetic NPs 18 , 19 , and the promotion of anti-tumor cytotoxic T cells' function by granzyme B NPs 20 , as well as the augmented cytotoxic T cells recruitment to tumor site by antibody-targeted NPs 21 . Moreover, the expression of pro-phagocytic calreticulin, functioning as an “eat me” signal, can be amplified on cancer cells by manganese-based NPs 22 .…”

Layer-by-Layer assembled nano-drug delivery systems for cancer treatment

“…For example, near-infrared cyanine dyes can be used to assembled into LbL NDDS modify chitosan. The resultant anticancer drug-loaded LbL assembled NDDS can therefore generate active singlet oxygen under near-infrared irradiation and can be used as novel vehicles for the combination of chemotherapy, photothermal therapy (PTT) and photodynamic therapy (PDT) (Chi et al., 2020 ; Shen et al., 2020 ). Besides, aiming at developing methods to speed up and scale up the LbL fabrication process, several techniques directly derived or inspired by the LbL methods are worth considering, such as controlled precipitation (Han et al., 2012 ), core-mediated in situ PE coacervation (Topbas et al., 2020 ), polymerization on the surfaces of templates and infiltration and cross-linking on porous templates (Correa et al., 2016 ; Lyons et al., 2019 ; Zhang et al., 2019 ).…”

Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?

“…As indicated above, efforts have also been made to overcome tumor hypoxia, which is a resistance mechanism to both PDT (due to the low tissue O 2 concentration) and immunotherapies (for a review, see [96] and the references therein); researchers have developed oxygen carriers including iron(III) oxide clusters or manganese dioxide (MnO 2 ). Lin et al integrated the benzoporphyrin PS with Fe 3 O as metal clusters in the core of porous nMOFs.…”

“…In addition, this nanoparticle also triggered cell surface exposure of CALR, as well as an abscopal effect in tumor-bearing mice, which likely increased the efficacy of ICIs through a more important recruitment of CD4 + and CD8 + cytotoxic T-cell populations in the tumors [97]. In a recent study, an alternative strategy relied on the generation of MnO 2 @Chitosan-CyI (MCC) nanosystems, by adsorbing chitosan and an iodinated derivative of cyanine dye (ICy) on MnO 2 nanoparticles [96]. ICy is derived from the FDA-approved indocyanine green and has a singlet oxygen quantum yield of 75% under NIR activation.…”