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Immunotherapy holds great promise for the treatment of aggressive and metastatic cancers; however, currently available immunotherapeutics, such as immune checkpoint blockade, benefit only a small subset of patients. A photoactivatable toll-like receptor 7/8 (TLR7/8) nanoagonist (PNA) system that imparts near-infrared (NIR) light-induced immunogenic cell death (ICD) in dying tumor cells in synchrony with the spontaneous release of a potent immunoadjuvant is developed here. The PNA consists of polymer-derived proimmunoadjuvants ligated via a reactive oxygen species (ROS)-cleavable linker and polymer-derived photosensitizers, which are further encapsulated in amphiphilic matrices for systemic injection. In particular, conjugation of the TLR7/8 agonist resiquimod to biodegradable macromolecular moieties with different molecular weights enabled pharmacokinetic tuning of small-molecule agonists and optimized delivery efficiency in mice. Upon NIR photoirradiation, PNA effectively generated ROS not only to ablate tumors and induce the ICD cascade but also to trigger the on-demand release of TLR agonists. In several preclinical cancer models, intravenous PNA administration followed by NIR tumor irradiation resulted in remarkable tumor regression and suppressed postsurgical tumor recurrence and metastasis. Furthermore, this treatment profoundly shifted the tumor immune landscape to a tumoricidal one, eliciting robust tumor-specific T cell priming in vivo. This work highlights a simple and cost-effective approach to generate in situ cancer vaccines for synergistic photodynamic immunotherapy of metastatic cancers.
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Neoplasias , Receptor 7 Toll-Like , Animais , Camundongos , Receptor 7 Toll-Like/agonistas , Espécies Reativas de Oxigênio , Imunoterapia/métodos , Neoplasias/terapia , Adjuvantes Imunológicos , Polímeros/química , Vacinação , Linhagem Celular TumoralRESUMO
The aggregation-caused quenching has always limited the high concentration and solid-state applications of carbon nanodots. While the aggregation-induced emission effect, dominated by intramolecular motion, may be an effective means to solve this problem. Here, hydrophobic solid-state red-light carbon nanodots (M-CDs) with 95% yield are synthesized by a one-step hydrothermal method using 2,2'-dithiodibenzoic acid as the carbon source and manganese acetate as the dopant source. The disulfide bond of 2,2'-dithiodibenzoic acid serves as the symmetry center of molecular rotation and Mn catalyzes the synthesis of M-CDs, which promotes the formation of the central graphitic carbon structure. The M-CDs/agar hydrogel composites can achieve fluorescence transition behavior because of the special fluorescence transition properties of M-CDs. When this composite hydrogel is placed in water, water molecules contact with M-CDs through the network structure of the hydrogels, making the aggregated hydrogels of M-CDs fluorescence orange-red under 365 nm excitation. While in dimethyl sulfoxide, water molecules in the hydrogels network are replaced and the M-CDs fluoresce blue when dispersed, providing a potential application in information encryption. In addition, high-performance monochromatic light-emitting diode (LED) devices are prepared by compounding M-CDs with epoxy resin and coating them on 365 nm LED chips.
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Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor (CAR) T cells have received clinical approval for monotherapy and combination treatment in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate a durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs), have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here, we review the current development of STING-activating therapeutics in both preclinical and clinical stages.
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Optical nanoparticles are promising diagnostic tools; however, their shallow optical imaging depth and slow clearance from the body have impeded their use for in vivo disease detection. To address these limitations, we develop activatable polyfluorophore nanosensors with biomarker-triggered nanoparticle-to-molecule pharmacokinetic conversion and near-infrared fluorogenic turn-on response. Activatable polyfluorophore nanosensors can accumulate at the disease site and react with disease-associated proteases to undergo in situ enzyme-catalysed depolymerization. This disease-specific interaction liberates renal-clearable fluorogenic fragments from activatable polyfluorophore nanosensors for non-invasive longitudinal urinalysis and outperforms the gold standard blood and urine assays, providing a level of sensitivity and specificity comparable to those of invasive biopsy and flow cytometry analysis. In rodent models, activatable polyfluorophore nanosensors enable ultrasensitive detection of tumours (1.6 mm diameter) and early diagnosis of acute liver allograft rejection. We anticipate that our modular nanosensor platform may be applied for early diagnosis of a range of diseases via a simple urine test.
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Nanopartículas , Neoplasias , Aloenxertos , Detecção Precoce de Câncer , Humanos , RimRESUMO
Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well-established to have antitumour and anti-fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF-LA@DSPE-PEG and MMF-LA@PEG-PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k -PLA8k and DSPE- PEG2k , respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti-HCC efficacy of nanoparticles (NPs), whereas NIH-3T3 fibroblasts and highly-fibrotic HCC models were used to explore the anti-fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF-LA@DSPE-PEG achieved significantly higher anti-HCC efficacy than free MMF and MMF-LA@PEG-PLA both in C57BL/6 HCC model and highly-fibrotic HCC models. Immunohistochemistry further confirmed that MMF-LA@DSPE-PEG dramatically reduced cancer-associated fibroblast (CAF) density in tumours, as the expression levels of alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF-LA@DSPE-PEG might act as a rational therapeutic strategy in treating HCC and preventing post-transplant HCC recurrence.
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Carcinoma Hepatocelular/tratamento farmacológico , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Ácido Micofenólico/farmacologia , Nanopartículas/uso terapêutico , Actinas/metabolismo , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Colágeno/metabolismo , Modelos Animais de Doenças , Endopeptidases/metabolismo , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Ácido Linoleico/química , Neoplasias Hepáticas/tratamento farmacológico , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Nanopartículas/química , Polímeros/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.
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Transplante de Coração , Transplante de Células-Tronco Hematopoéticas , Nanopartículas , Pró-Fármacos , Animais , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunossupressores , Camundongos , Serina-Treonina Quinases TORRESUMO
Axon growth and neuronal apoptosis are considered to be crucial therapeutic targets against spinal cord injury (SCI). Growing evidences have reported stimulation of glucagon-like peptide-1 (GLP-1)/GLP-1 receptor (GLP-1R) signalling axis provides neuroprotection in experimental models of neurodegeneration disease. Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP4), resulting in blocking of GLP-1/GLP1R signalling process. Sitagliptin, a highly selective inhibitor of DPP4, has approved to have beneficial effects on diseases in which neurons damaged. However, the roles and the underlying mechanisms of sitagliptin in SCI repairing remain unclear. In this study, we used a rat model of SCI and PC12 cells/primary cortical neurons to explore the mechanism of sitagliptin underlying SCI recovery. We discovered the expression of GLP-1R decreased in the SCI model. Administration of sitagliptin significantly increased GLP-1R protein level, alleviated neuronal apoptosis, enhanced axon regeneration and improved functional recovery following SCI. Nevertheless, treatment with exendin9-39, a GLP-1R inhibitor, remarkably reversed the protective effect of sitagliptin. Additionally, we detected the AMPK/PGC-1α signalling pathway was activated by sitagliptin stimulating GLP-1R. Taken together, sitagliptin may be a potential agent for axon regrowth and locomotor functional repair via GLP-1R-induced AMPK/ PGC-1α signalling pathway after SCI.
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Apoptose/efeitos dos fármacos , Axônios/efeitos dos fármacos , Axônios/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Regeneração Nervosa/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/reabilitação , Animais , Biomarcadores , Células Cultivadas , Modelos Animais de Doenças , Feminino , Imunofluorescência , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Locomoção/efeitos dos fármacos , Locomoção/genética , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Ratos , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologiaRESUMO
In this study, we newly designed and synthesized a small library of ten structurally related C,N-cyclometalated ruthenium(II) complexes containing various pyridine-functionalized NHC ligand and chelating bipyridyl ligands (e.g., 2,2'-bipyridine, 5,5'-dimethyl-2,2'-bipyridine, and 1,10-phenanthroline (phen)). The complexes were well characterized by NMR, electrospray ionization-mass spectrometry, and single-crystal X-ray structure analyses. Among the new ruthenium(II) derivatives, we identified that the complex Ru8 bearing bulky moieties (i.e., phen and pentamethyl benzene) had the most potent cytotoxicity against all tested cancer cell lines, generating dose- and cell line-dependent IC50 values at the range of 3.3-15.0â µm. More significantly, Ru8 not only efficiently inhibited the metastasis process against invasion and migration of tumor cells but also exhibited potent antivascular effects by suppressing HUVEC cells migration and tube formation in vitro and blocking vessel generation in vivo (chicken chorioallantoic membrane model). In a metastatic A2780 tumor xenograft-bearing mouse model, administration of Ru8 outperformed antimetastatic agent NAMI-A and clinically approved cisplatin in terms of antitumor efficacy and inhibition of metastases to other organs. Overall, these data provided compelling evidence that the new cyclometalated ruthenium complex Ru8 is an attractive agent because of synergistically suppressing bulky tumors and metastasized tumor nudes. Therefore, the complex Ru8 deserves further investigations.
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Antineoplásicos , Cisplatino/química , Compostos Organometálicos , Neoplasias Ovarianas , Rutênio , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Compostos Organometálicos/metabolismo , Rutênio/farmacologiaRESUMO
Homologous recombination (HR), which mediates the repair of DNA double-strand breaks (DSB), is crucial for maintaining genomic integrity and enhancing survival in response to chemotherapy and radiotherapy in human cancers. However, the mechanisms of HR repair in treatment resistance for the improvement of cancer therapy remains unclear. Here, we report that the zinc finger protein 830 (ZNF830) promotes HR repair and the survival of cancer cells in response to DNA damage. Mechanistically, ZNF830 directly participates in DNA end resection via interacting with CtIP and regulating CtIP recruitment to DNA damage sites. Moreover, the recruitment of ZNF830 at DNA damage sites is dependent on its phosphorylation at serine 362 by ATR. ZNF830 directly and preferentially binds to double-strand DNA with its 3' or 5' overhang through the Zinc finger (Znf) domain, facilitating HR repair and maintaining genome stability. Thus, our study identified a novel function of ZNF830 as a HR repair regulator in DNA end resection, conferring the chemoresistance to genotoxic therapy for cancers those that overexpress ZNF830.
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DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Kruppel-Like/genética , Neoplasias Pulmonares/genética , Reparo de DNA por Recombinação , Neoplasias Gástricas/genética , Animais , Antineoplásicos/uso terapêutico , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sítios de Ligação , Camptotecina/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Quebras de DNA de Cadeia Dupla , DNA de Neoplasias/metabolismo , Endodesoxirribonucleases , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Instabilidade Genômica , Humanos , Hidroxiureia/uso terapêutico , Fatores de Transcrição Kruppel-Like/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Nus , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Fosforilação , Ligação Proteica , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An efficient annulation of α-imino rhodium carbenes with α,ß-unsaturated ketones has been developed to generate multisubstituted 2,3-dihydropyrrole derivatives. Using the optimized catalyst, this approach is compatible with both cyclic and normal linear α,ß-unsaturated ketones. Further detosylation in the presence of base could produce multisubstituted pyrroles. The new method has the potential to enable the rapid construction of bioactive molecules containing pyrrole rings.
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BACKGROUND AND AIM: Our previous proteomic research found that chloride intracellular channel 1 (CLIC1) was upregulated in hepatocellular carcinoma (HCC) tissues with portal vein tumor thrombus. The present study aimed to determine the role of CLIC1 in HCC invasion. METHODS: Immunohistochemistry was used to explore protein expression of CLIC1 in 15 cirrhotic tissues and 69 pairs of HCC and paracarcinoma tissues. Small interfering RNA (siRNA) and plasmids were transfected into HepG2 and SMMC7721 cells, and the in vitro function of CLIC1 in these cells were assessed with cell counting kit-8 assays, cell apoptosis assays, scratch assays, and transwell assays. Microarray analysis was also performed to further explore the candidate genes related to CLIC1. RESULTS: Our results confirmed that upregulated CLIC1 expression was significantly correlated with vascular invasion (P = 0.034) in HCC tissues. Knockdown of CLIC1 decreased cell viability and the invasive potency of HepG2 cells, whereas CLIC1 overexpression resulted in an opposite effect in SMMC7721 cells. Microarray analysis identified 618 genes that were differentially expressed (fold change ≥ 2, P < 0.05) between HepG2 cells transfected with CLIC1 siRNA and the negative control. Further studies indicate that knockdown of CLIC1 increased maspin expression and reduced vascular endothelial growth factor (VEGF), matrixmetalloproteinase-2 (MMP2), MMP9, MMP11, and MMP12 expression. In contrast, overexpression of CLIC1 decreased maspin expression and increased VEGF, MMP2, MMP12, and MMP13 expression. CONCLUSIONS: CLIC1 protein expression is significantly correlated with vascular invasion, and the present study suggests a previously unknown mechanism of CLIC1-mediated control of HCC invasiveness by targeting maspin.
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Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Canais de Cloreto/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Serpinas/genética , Serpinas/metabolismo , Adulto , Idoso , Carcinoma Hepatocelular/irrigação sanguínea , Movimento Celular , Feminino , Células Hep G2 , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genéticaRESUMO
A small library of water-soluble N-heterocyclic carbene (NHC)-stabilized palladium complexes was prepared and applied for cross-couplings of biomolecules under mild conditions in water. Pd-NHC complexes bearing hydrophilic groups were demonstrated to be efficient catalysts for the Suzuki-Miyaura coupling of various unnatural amino acids and proteins bearing p-iodophenyl functional groups. We further utilized this catalytic system for the rapid bioorthogonal labeling of proteins on the surfaces of mammalian cells. These results demonstrated that NHC-stabilized metal complexes have potential utility in cellular systems.
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Compostos Heterocíclicos/química , Metano/análogos & derivados , Compostos Organometálicos/química , Paládio/química , Catálise , Metano/química , Estrutura MolecularRESUMO
Drug-loaded nanoparticles (NPs) are of particular interest for efficient cancer therapy due to their improved drug delivery and therapeutic index in various types of cancer. However, the encapsulation of many chemotherapeutics into delivery NPs is often hampered by their unfavorable physicochemical properties. Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties. This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures. Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.
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Antineoplásicos/administração & dosagem , Camptotecina/análogos & derivados , Portadores de Fármacos , Polímeros/química , Pró-Fármacos/química , Antineoplásicos/farmacologia , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Irinotecano , Microscopia Eletrônica de Transmissão , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologiaRESUMO
Although organ transplantation is a life-saving medical procedure, the challenge of posttransplant rejection necessitates safe and effective immune modulation strategies. Nanodelivery approaches may have the potential to overcome the limitations of small-molecule immunosuppressive drugs, achieving efficacious treatment options for transplant tolerance without compromising overall host immunity. This review highlights recent advances in biomaterial-assisted formulations and technologies for targeted nanodrug delivery with transplant organ- or immune cell-level precision for treating graft rejection after transplantation. We provide an overview of the mechanism of transplantation rejection, current clinically approved immunosuppressive drugs, and their relevant limitations. Finally, we discuss the targeting principles and advantages of organ- and immune cell-specific delivery technologies. The development of biomaterial-assisted novel therapeutic strategies holds considerable promise for treating organ rejection and clinical translation.
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Therapeutic strategies that induce inflammatory responses in immunologically "cold" tumors have the potential to improve immunotherapeutic outcomes. Pharmacologically activating the STING pathway induces innate immunity, subsequently enhancing tumor immunogenicity. Here, we developed a nanoadjuvant with tumor-restricted pharmacology that rapidly activated STING and reshaped the tumor microenvironment (TME). The non-nucleotide STING agonist MSA-2 was chemically engineered with a piperazine motif linked by a saturated hydrocarbon chain of varying lengths to produce ionizable prodrugs that were further developed into nanoadjuvants. Compared with state-of-the-art liposomes, the nanoadjuvant displayed prolonged retention in the circulation and improved intratumoral delivery. In the acidic TME, the nanoadjuvant underwent polyethylene glycol deshielding, enabling efficient extravasation and penetration into tumors. Concomitantly, the STING prodrug escaped from the endo/lysosome compartment to partition into the cytosol for spontaneous esterase-catalyzed drug activation. In mouse models of syngeneic and chemically induced colorectal cancers, nanoparticle treatment provoked robust STING-mediated antitumor immunity, shifting the tumor immune landscape from immunosuppressed to tumoricidal. Additionally, the nanoadjuvant demonstrated antitumor efficacy in triple-negative breast cancer, which was further enhanced by the addition of immune checkpoint inhibitors. Collectively, this study demonstrates the safety and immune stimulating effects of a STING-activating nanoadjuvant, supporting the clinical evaluation of this STING immunotherapeutic alone and in combination with other immunotherapies.
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Organ transplantation is the preferred paradigm for patients with end-stage organ failures. Despite unprecedented successes, complications such as immune rejection, ischemia-reperfusion injury, and graft dysfunction remain significant barriers to long-term recipient survival after transplantation. Conventional immunosuppressive drugs have limited efficacy because of significant drug toxicities, high systemic immune burden, and emergence of transplant infectious disease, leading to poor quality of life for patients. Nanoparticle-based drug delivery has emerged as a promising medical technology and offers several advantages by enhancing the delivery of drug payloads to their target sites, reducing systemic toxicity, and facilitating patient compliance over free drug administration. In addition, nanotechnology-based imaging approaches provide exciting diagnostic methods for monitoring molecular and cellular changes in transplanted organs, visualizing immune responses, and assessing the severity of rejection. These noninvasive technologies are expected to help enhance the posttransplantation patient survival through real time and early diagnosis of disease progression. Here, we present a comprehensive review of nanotechnology-assisted strategies in various aspects of organ transplantation, including organ protection before transplantation, mitigation of ischemia-reperfusion injury, counteraction of immune rejection, early detection of organ dysfunction posttransplantation, and molecular imaging and diagnosis of immune rejection.
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Rejeição de Enxerto , Imagem Molecular , Transplante de Órgãos , Traumatismo por Reperfusão , Humanos , Transplante de Órgãos/efeitos adversos , Imagem Molecular/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/imunologia , Nanotecnologia/métodos , Animais , Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Sobrevivência de Enxerto , Valor Preditivo dos Testes , Nanomedicina/métodos , Nanopartículas , Resultado do TratamentoRESUMO
Effective anticancer immunity depends on properly activating multiple stepwise events in the cancer-immunity cycle. An immunologically "cold" tumor microenvironment (TME) engenders immune evasion and refractoriness to conventional checkpoint blockade immunotherapy. Here, we combine nanoparticle formulations and an in situ formed hydrogel scaffold to treat accessible tumors locally and to stimulate systemic immunity against metastatic tumor lesions. The nanoparticles encapsulate poly(ε-caprolactone)-derived cytotoxic chemotherapy and adjuvant of Toll-like receptor 7/8 through a reactive oxygen species (ROS)-cleavable linker that can be self-activated by the coassembled neighboring photosensitizer following near-infrared (NIR) laser irradiation. Further development results in syringeable, NIR light-responsive, and immunogenic hydrogel (iGEL) that can be implanted peritumorally and deposited into the tumor surgical bed. Upon NIR laser irradiation, the generated ROS induces iGEL degradation and bond cleavage in the polymer-drug conjugates, triggering the immunogenic cell death cascade in cancer cells and spontaneously releasing encapsulated agents to rewire the cancer-immunity cycle. Notably, upon application in multiple preclinical models of melanoma and triple-negative breast cancer, which are aggressive and refractory to conventional immunotherapy, iGEL induces durable remission of established tumors, extends postsurgical tumor-free survival, and inhibits metastatic burden. The result of this study is a locally administrable immunogenic hydrogel for triggering host systemic immunity to improve immunotherapeutic efficacy with minimal off-target side effects.
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Hidrogéis , Raios Infravermelhos , Animais , Camundongos , Hidrogéis/química , Humanos , Antineoplásicos/química , Antineoplásicos/farmacologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Nanopartículas/química , Linhagem Celular Tumoral , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Camundongos Endogâmicos C57BL , Imunoterapia , Feminino , Poliésteres/químicaRESUMO
The immunosuppressive tumor microenvironment (TME) remains a major obstacle to tumor control and causes suboptimal responses to immune checkpoint blockade (ICB) therapy. Thus, developing feasible therapeutic strategies that trigger inflammatory responses in the TME could improve the ICB efficacy. Mitochondria play an essential role in inflammation regulation and tumor immunogenicity induction. Herein, we report the discovery and characterization of a class of small molecules that can recapitulate aqueous self-assembly behavior, specifically target cellular organelles (e.g., mitochondria), and invigorate tumor cell immunogenicity. Mechanistically, this nanoassembly platform dynamically rewires mitochondria, induces endoplasmic reticulum stress, and causes apoptosis/paraptosis-associated immunogenic cell death. After treatment, stressed and dying tumor cells can act as prophylactic or therapeutic cancer vaccines. In preclinical mouse models of cancers with intrinsic or acquired resistance to PD-1 blockade, the local administration of nanoassemblies inflames the immunologically silent TME and synergizes with ICB therapy, generating potent antitumor immunity. This chemically programmed small-molecule immune enhancer acts distinctly from regular cytotoxic therapeutics and offers a promising strategy for synchronous and dynamic tailoring of innate immunity to achieve traceless cancer therapy and overcome immunosuppression in cancers.
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Mitocôndrias , Neoplasias , Microambiente Tumoral , Animais , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Camundongos , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Humanos , Linhagem Celular Tumoral , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/imunologia , Apoptose/efeitos dos fármacos , Feminino , Morte Celular Imunogênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/administração & dosagem , Imunoterapia/métodosRESUMO
Phase-transformable ionic conductors (PTICs) show significant prospects for functional applications due to their reversible resistance switching property. However, the representative design principle of PTICs is utilizing the melt-crystallization transition of ionic liquids, and the resistance switching temperatures of such PTICs cannot be tuned as desired. Herein, a new strategy is proposed to design PTICs with on-demand resistance switching temperatures by using the melt-crystallization transition of polymer cocrystal phase, whose melting temperature shows a linear relationship with the polymer compositions. Owing to the melt of polymer cocrystal domains and the tunable migration of ions in the resistance switching region, the obtained PTICs display ultrahigh temperature sensitivity with a superior temperature coefficient of resistance of -8.50% °C-1 around human body temperature, as compared to various ionic conductors previously reported. Therefore, the PTICs can detect tiny temperature variation, allowing for the intelligent applications for overheating warning and heat dissipation. It is believed that this work may inspire future researches on the development of advanced soft electrical devices.
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BACKGROUND: Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. METHODS: Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. FINDINGS: Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ+CD8+ T cells and CD8+ memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy. INTERPRETATION: The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents. FUNDING: This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).