Tumor resistance to chemotherapy is the major obstacle to employ cisplatin, one of the broadly used chemotherapeutic drugs, for effective treatment of various tumors in the clinic. Most acknowledged mechanisms of cancer resistance to cisplatin focus on increased nuclear DNA repair or detoxicity of cisplatin. We previously demonstrated that there was a unique metabolic profile in cisplatinresistant (CP-r) human epidermoid adenocarcinoma KB-CP 20 and hepatoma BEL 7404-CP 20 cancer cells. In this study, we further defined hyperpolarized mitochondrial membrane potentials (Δψm) in CP-r KB-CP 20 and BEL 7404-CP 20 cells compared to the cisplatin-sensitive (CP-s) KB-3-1 and BEL 7404 cells. Based on the mitochondrial dysfunction, mitaplatin was designed with two mitochondrial-targeting moieties [dichloroacetate (DCA) units] to the axial positions of a six-coordinate Pt(IV) center to sensitize cisplatin resistance. It was found that mitaplatin induced more apoptosis in CP-r KB-CP 20 and BEL 7404-CP 20 cells than that of cisplatin, DCA and cisplatin/DCA compared on an equal molar basis. There was more platinum accumulation in mitaplatin-treated CP-r cells due to enhanced transmembrane permeability of lipophilicity, and mitaplatin also showed special targeting to mitochondria. Moreover, in the case of treatment with mitaplatin, the dramatic collapse of Δψm was shown in a dose-dependent manner, which was confirmed by FACS and confocal microscopic measurements. Reduced glucose utilization of CP-r cells was detected with specifically inhibited phosphorylation of pyruvate dehydrogenase (PDH) at Ser-232, Ser-293, and Ser-300 of the E1α subunit when treated with mitaplatin, which was indicated to modulate the abnormal glycolysis of resistant cells. The present study suggested novel mitochondrial mechanism of mitaplatin circumventing cisplatin resistance toward CP-r cells as a carrier across membrane to produce CP-like cytotoxicity and DCA-like mitochondria-dependent apoptosis. Therefore, mitochondria targeting compounds would be more vulnerable and selective to overcome cisplatin resistance due to the unique metabolic properties of CP-r cancer cells.
A versatile and highly effective platform remains a major challenge in the development of personalized cancer vaccines. Here, we devised a redox-responsive polycondensate neoepitope (PNE) through a reversible polycondensation reaction of peptide neoantigens and adjuvants together with a tracelessly responsive linker-monomer. Peptide-based neoantigens with diverse sequences and structures could be copolymerized with molecular adjuvants to form PNEs of high loading capacity for vaccine delivery without adding any carriers. The redox-responsive PNEs with controlled molecular weights and sizes efficiently targeted and accumulated in draining lymph nodes and greatly promoted the antigen capture and cross-presentation by professional antigen presenting cells. Mice immunized with PNEs showed markedly enhanced antigen-specific T cell response and the protective immunity against the tumor cell challenge.
Mitochondria‐targeted photodynamic therapy (Mt‐PDT), which enables the photogenerated cytotoxic oxygen species with fatal oxidative damage to block mitochondrial functions, has been considered as a promising method to enhance the anticancer effectiveness. Aiming at the challenges of PDT, in the past few decades, numerous mitochondria‐targeting molecular agents have been developed to boost the PDT efficacy via directly destroying the mitochondria or activating mitochondria‐mediated cell death pathways. Herein, a review for recent advances of Mt‐PDT is highlighted including: mitochondrial targeting design principles and strategies, therapeutic performance of mitochondria‐targeted agents‐mediated PDT as well as the agent‐free Mt‐PDT. In addition, it puts together the achievements of the combinatory mitochondria‐anchoring PDT and other anticancer strategies, demonstrating the advantages provided by Mt‐PDT. The existing challenges are discussed and future settlements for the development of mitochondria‐specific agents are also forecasted.
Targeting the stimulator of interferon genes (STING) pathway with cyclic dinucleotides (CDNs), the natural STING agonists, is a promising immunotherapeutic strategy for cancer. However, the clinical application of natural CDNs as therapeutics is greatly hindered by their intrinsic properties including negative charges, small molecular weight, and high susceptibility to enzymatic degradation. Mn 2+ ions have been recently discovered to directly activate the cyclic GMP-AMP (cGAMP) synthase (cGAS) and augment cGAMP-STING binding affinity. Here, a PEGylated manganese(II) phosphate (MnP-PEG) nanocluster is developed with high biocompatibility and potent capacity to stimulate the cGAS-STING pathway. MnP-PEG nanoclusters activate the immature bone marrow-derived dendritic cells (DCs) leading to 57.3-and 13.3-fold higher production of interferon and interleukin-6 than free cGAMP, respectively. The potent STING activation capacity is likely due to the efficient cellular internalization of MnP-PEG nanoclusters by DCs and acid-triggered release of Mn 2+ ions in the endolysosomes. Intratumoral administration of MnP-PEG nanoclusters markedly enhances tumor infiltration as well as maturation of DCs and macrophages, and promotes activation and cytotoxicity of T cells and natural killer cells in the tumor. MnP-PEG nanocluster in combination with a checkpoint inhibitor leads to significant tumor regression in the B16F10 murine melanoma model without any overt toxicities.
Immune stimulatory antibodies and cytokines elicit potent antitumor immunity. However, the dose-limiting systemic toxicity greatly hinders their clinical applications. Here, we demonstrate a chemical approach, termed "switchable" immune modulator (Sw-IM), to limit the systemic exposure and therefore ameliorate their toxicities. Sw-IM is a biomacromolecular therapeutic reversibly masked by biocompatible polymers through chemical linkers that are responsive to tumor-specific stimuli, such as high reducing potential and acidic pH. Sw-IMs stay inert (switch off) in the circulation and healthy tissues but get reactivated (switch on) selectively in tumor via responsive removal of the polymer masks, thus focusing the immune boosting activities in the tumor microenvironment. Sw-IMs applied to anti-4-1BB agonistic antibody and IL-15 cytokine led to equivalent antitumor efficacy to the parental IMs with markedly reduced toxicities. Sw-IM provides a highly modular and generic approach to improve the therapeutic window and clinical applicability of potent IMs in mono-and combinational immunotherapies.
Cancer vaccine aiming to expand the pool or increase the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison with other immunotherapies such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and the inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges remain to develop a highly efficient and safe delivery strategy to target cancer vaccines to professional antigen presenting cells and elicit optimized immune response against cancer. To meet these challenges, biomaterials, in particular, the ones that are designed to respond to certain environmental stimuli, termed stimuli-responsive biomaterials, are being actively developed in order to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines with the focus on the chemistry and material design with various responsiveness. We also discuss the challenges and opportunities currently facing the field and provide a perspective for future directions.
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