RESUMO
Tumor hypoxia and acidity are well-known features in solid tumors that cause immunosuppression and therapeutic resistance. Herein, we rationally synthesized a multifunctional fluorinated calcium carbonate (fCaCO3) nanoregulator by coating CaCO3 nanoparticles with dopamine-grafted perfluorosebacic acid (DA2-PFSEA) and ferric ions by utilizing their coordination interaction. After PEGylation, the obtained fCaCO3-PEG showed high loading efficacy to perfluoro-15-crown-5-ether (PFCE), a type of perfluorocarbon with high oxygen solubility, thereby working as both oxygen nanoshuttles and proton sponges to reverse tumor hypoxia and acidity-induced resistance to radiotherapy. The as-prepared PFCE@fCaCO3-PEG could not only function as long-circulating oxygen nanoshuttles to attenuate tumor hypoxia but also neutralize the acidic tumor microenvironment by restricting the production of lactic acid and reacting with extracellular protons. As a result, treatment with PFCE@fCaCO3-PEG could improve the therapeutic outcome of radiotherapy toward two murine tumors with distinct immunogenicity. The PFCE@fCaCO3-PEG-assisted radiotherapy could also collectively inhibit the growth of unirradiated tumors and reject rechallenged tumors by synergistically eliciting protective antitumor immunity. Therefore, our work presents the preparation of fluorinated CaCO3 nanoregulators to reverse tumor immunosuppression and potentiate radiotherapy through chemically modulating tumor hypoxic and acidic microenvironments tightly associated with tumor glucose metabolism.
Assuntos
Fluorocarbonos , Nanopartículas , Neoplasias , Animais , Carbonato de Cálcio , Linhagem Celular Tumoral , Dopamina , Glucose , Ácido Láctico , Camundongos , Neoplasias/metabolismo , Oxigênio , Prótons , Microambiente TumoralRESUMO
Vitamin C (VitC) has shown great promise to promote cancer immunotherapy, however, its high hydrophilicity makes it quickly excreted, leading to limited therapeutic efficiency even with frequent high-dose administration. Herein, we provide a pioneering report about the employment of VitC amphiphile self-assembled nanofiber hydrogels for enhanced cancer immunotherapy. Specifically, driven by hydrogen bonding and hydrophobic interactions, the synthesized VitC amphiphile, consisting of a hydrophilic VitC headgroup and a hydrophobic alkyl chain, could self-assemble into an injectable nanofiber hydrogel with self-healing properties. The formed VitC hydrogel not only serves as a reservoir for VitC but also acts as an effective delivery platform for stimulator of interferon genes (STING) agonist-4 (SA). Interestingly, the VitC hydrogel itself exhibits antitumor effects by upregulating genes related to interferon (IFN) signaling, apoptotic signaling and viral recognition and defense. Moreover, the SA-encapsulated VitC hydrogel (SA@VitC hydrogel) synergistically activated the immune system to inhibit the progression of both local and abscopal tumors.
RESUMO
Platinum complexes, despite being the most successful organometallic anticancer chemotherapy drugs, still suffer from serious side effects and therapy resistance. Inspired by the immunomodulation effect of platinum drugs, an epigenetic platinum(IV) complex was synthesized for enhanced cancer chemoimmunotherapy by conjugating oxidized oxaliplatin (OXA) with 2-bromo-1-(3,3-dinitro-1-azetidinyl)ethenone (RRx-001), the latter of which as a nitric oxide (NO) donor is also an epigenetic agent. The obtained complex (named OXA-NO) could significantly increase the level of "eat me" signal CRT expression and decrease the level of "don't eat me" signal CD47 expression on cancer cell membranes to promote their phagocytosis by macrophages. In addition, OXA-NO could release nitric oxide to trigger the transformation of pro-tumorigenic M2-type macrophages into antitumor M1-type macrophages within the tumor to reverse the immunosuppressive tumor microenvironment. Compared to commercial OXA, OXA-NO exhibited much stronger tumor growth inhibition ability and was much better tolerated, with obviously weakened side effects observed in spleen, lung, and kidneys. Therefore, this epigenetic platinum(IV) complex that exhibits excellent therapeutic efficacy and safety has great potential in the clinic.
Assuntos
Neoplasias , Platina , Epigênese Genética , Humanos , Neoplasias/tratamento farmacológico , Óxido Nítrico , Fagocitose , Platina/uso terapêutico , Microambiente TumoralRESUMO
Chemotherapeutic agents have been widely used for cancer treatment in clinics. Aside from their direct cytotoxicity to cancer cells, some of them could activate the immune system of the host, contributing to the enhanced antitumor activity. Here, the reactive oxygen species (ROS)-responsive hydrogel, covalently cross-linked by phenylboronic acid-modified 7-ethyl-10-hydroxycamptothecin (SN38-SA-BA) with poly(vinyl alcohol) (PVA), is fabricated for topical delivery of anti-programmed cell death protein ligand 1 antibodies (aPDL1). In the presence of endogenous ROS, SN38-SA-BA will be oxidized and hydrolyzed, leading to the degradation of hydrogel and the release of initial free SN38 and encapsulated aPDL1. It is demonstrated that SN38 could elicit specific immune responses by triggering immunogenic cell death (ICD) of cancer cells, a distinct cell death pathway featured with the release of immunostimulatory damage-associated molecular patterns (DAMPs). Meanwhile, the released aPDL1 could bind to programmed cell death protein ligand 1 (PDL1) expressed on cancer cells to augment antitumor T cell responses. Thus, the ROS-responsive prodrug hydrogel loaded with aPDL1 could induce effective innate and adaptive antitumor immune responses after local injection, significantly inhibiting or even eliminating those tumors.
Assuntos
Antineoplásicos/farmacologia , Imunoterapia , Irinotecano/farmacologia , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Ácidos Borônicos/química , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada , Feminino , Irinotecano/química , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Tamanho da Partícula , Álcool de Polivinil/química , Pró-Fármacos/síntese química , Pró-Fármacos/química , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Espécies Reativas de Oxigênio/imunologia , Propriedades de Superfície , Linfócitos T/imunologiaRESUMO
Due to the negative roles of tumor microenvironment (TME) in compromising therapeutic responses of various cancer therapies, it is expected that modulation of TME may be able to enhance the therapeutic responses during cancer treatment. Herein, we develop a concise strategy to prepare pH-responsive nanoparticles via the CaCO3-assisted double emulsion method, thereby enabling effective co-encapsulation of both doxorubicin (DOX), an immunogenic cell death (ICD) inducer, and alkylated NLG919 (aNLG919), an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1). The obtained DOX/aNLG919-loaded CaCO3 nanoparticles (DNCaNPs) are able to cause effective ICD of cancer cells and at the same time restrict the production of immunosuppressive kynurenine by inhibiting IDO1. Upon intravenous injection, such DNCaNPs show efficient tumor accumulation, improved tumor penetration of therapeutics and neutralization of acidic TME. As a result, those DNCaNPs can elicit effective anti-tumor immune responses featured in increased density of tumor-infiltrating CD8+ cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing the growth of subcutaneous CT26 and orthotopic 4T1 tumors on the Balb/c mice through combined chemotherapy & immunotherapy. This study presents a compendious strategy for construction of pH-responsive nanoparticles, endowing significantly enhanced chemo-immunotherapy of cancer by overcoming the immunosuppressive TME.