RESUMO
Systemic antiplatelet treatment represents a promising option to improve the therapeutic outcomes and therapeutic efficacy of chemotherapy and immunotherapy due to the critical contribution of platelets to tumour progression. However, until recently, targeting platelets as a cancer therapeutic has been hampered by the elevated risk of haemorrhagic and thrombocytopenic (low platelet count) complications owing to the lack of specificity for tumour-associated platelets. Recent work has advanced our understanding of the molecular mechanisms responsible for the contribution of platelets to tumour progression and metastasis. This has led to the identification of the biological changes in platelets in the presence of tumours, the complex interactions between platelets and tumour cells during tumour progression, and the effects of platelets on antitumour therapeutic response. In this Review, we present a detailed picture of the dynamic roles of platelets in tumour development and progression as well as their use in diagnosis, prognosis and monitoring response to therapy. We also provide our view on how to overcome challenges faced by the development of precise antiplatelet strategies for safe and efficient clinical cancer therapy.
Assuntos
Neoplasias , Humanos , Neoplasias/patologia , Plaquetas/patologia , Plaquetas/fisiologia , ImunoterapiaRESUMO
A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to be a critical earlier trigger for cancer-associated thrombus formation. However, there currently is no viable approach to monitor specific changes in tumor-associated platelet activity. Here, we describe a chromatograph-like microfluidic device that is highly sensitive to the activity status of peripheral circulating platelets in both tumor-bearing mice and clinical cancer patients. Our results show a strongly positive correlation between platelet activation status and tumor progression. Six-month follow-up data from advanced cancer patients reveal positive links between platelet activity level and thrombus occurrence rate, with a high predictive capacity of thrombotic events (AUC = 0.842). Our findings suggest that circulating platelet activity status determined by this microfluidic device exhibits sensitive, predictive potential for thrombotic events in cancer patients for directing well-timed antithrombosis treatment.
Assuntos
Neoplasias , Trombose , Camundongos , Animais , Plaquetas/patologia , Ativação Plaquetária/fisiologia , Trombose/etiologia , Neoplasias/complicaçõesRESUMO
Nanoparticles (NP) spanning diverse materials and properties have the potential to encapsulate and to protect a wide range of therapeutic cargos to increase bioavailability, to prevent undesired degradation, and to mitigate toxicity. Fulvestrant, a selective estrogen receptor degrader, is commonly used for treating patients with estrogen receptor (ER)-positive breast cancer, but its broad and continual application is limited by poor solubility, invasive muscle administration, and drug resistance. Here, we developed an active targeting motif-modified, intravenously injectable, hydrophilic NP that encapsulates fulvestrant to facilitate its delivery via the bloodstream to tumors, improving bioavailability and systemic tolerability. In addition, the NP was coloaded with abemaciclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), to prevent the development of drug resistance associated with long-term fulvestrant treatment. Targeting peptide modifications on the NP surface assisted in the site-specific release of the drugs to ensure specific toxicity in the tumor tissues and to spare normal tissue. The NP formulation (PPFA-cRGD) exhibited efficient tumor cell killing in both in vitro organoid models and in vivo orthotopic ER-positive breast cancer models without apparent adverse effects, as verified in mouse and Bama miniature pig models. This NP-based therapeutic provides an opportunity for continual and extensive clinical application of fulvestrant, thus indicating its promise as a treatment option for patients with ER-positive breast cancer. SIGNIFICANCE: A smart nanomedicine encapsulating fulvestrant to improve its half-life, bioavailability, and tumor-targeting and coloaded with CDK4/6 inhibitor abemaciclib to block resistance is a safe and effective therapy for ER-positive breast cancer.
Assuntos
Neoplasias , Receptores de Estrogênio , Animais , Camundongos , Suínos , Fulvestranto/farmacologia , Fulvestranto/uso terapêutico , Receptores de Estrogênio/metabolismo , Aminopiridinas/farmacologia , Neoplasias/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Linhagem Celular TumoralRESUMO
New strategies to decrease risk of relapse after surgery are needed for improving 5-year survival rate of hepatocellular carcinoma (HCC). To address this need, a wound-targeted nanodrug is developed, that contains an immune checkpoint inhibitor (anti-PD-L1)and an angiogenesis inhibitor (sorafenib)). These nanoparticles consist of highly biocompatible mesoporous silica (MSNP) that is surface-coated with platelet membrane (PM) to achieve surgical site targeting in a self-amplified accumulation manner. Sorafenib is introduced into the MSNP pores while covalently attaching anti-PD-L1 antibody on the PM surface. The resulting nano-formulation, abbreviated as a-PM-S-MSNP, can effectively target the surgical margin when intraperitoneally (IP) administered into an immune competent murine orthotopic HCC model. Multiple administrations of a-PM-S-MSNP generate potent anti-HCC effect and significantly prolong overall mice survival. Immunophenotyping and immunochemistry staining reveal the signatures of favorable anti-HCC immunity and anti-angiogenesis effect at tumor sites. More importantly, microscopic inspection of a-PM-S-MSNP treated mice shows that 2 out 6 are histologically tumor-free, which is in sharp contrast to the control mice where tumor foci can be easily identified. The data suggest that a-PM-S-MSNP can efficiently inhibit post-surgical HCC relapse without obvious side effects and holds considerable promise for clinical translation as a novel nanodrug.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/cirurgia , Linhagem Celular Tumoral , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/cirurgia , Camundongos , Nanopartículas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Sorafenibe/farmacologia , Sorafenibe/uso terapêuticoRESUMO
Selective occlusion of tumor vasculature has proven to be an effective strategy for cancer therapy. Among vascular coagulation agents, the extracellular domain of coagulation-inducing protein tissue factor, truncated tissue factor (tTF), is the most widely used. Since the truncated protein exhibits no coagulation activity and is rapidly cleared in the circulation, free tTF cannot be used for cancer treatment on its own but must be combined with other moieties. We here developed a novel, tumor-specific tTF delivery system through coupling tTF with the DNA aptamer, AS1411, which selectively binds to nucleolin receptors overexpressing on the surface of tumor vascular endothelial cells and is specifically cytotoxic to target cells. Systemic administration of the tTF-AS1411 conjugates into tumor-bearing animals induced intravascular thrombosis solely in tumors, thus reducing tumor blood supply and inducing tumor necrosis without apparent side effects. This conjugate represents a uniquely attractive candidate for the clinical translation of vessel occlusion agent for cancer therapy.
RESUMO
Compared with traditional chemotherapeutics, vascular disruption agents (VDAs) have the advantages of rapidly blocking the supply of nutrients and starving tumors to death. Although the VDAs are effective under certain scenarios, this treatment triggers angiogenesis in the later stage of therapy that frequently leads to tumor recurrence and treatment failure. Additionally, the nonspecific tumor targeting and considerable side effects also impede the clinical applications of VDAs. Here we develop a customized strategy that combines a VDA with an anti-angiogenic drug (AAD) using mesoporous silica nanoparticles (MSNs) coated with platelet membrane for the self-assembled tumor targeting accumulation. The tailor-made nanoparticles accumulate in tumor tissues through the targeted adhesion of platelet membrane surface to damaged vessel sites, resulting in significant vascular disruption and efficient anti-angiogenesis in animal models. This study demonstrates the promising potential of combining VDA and AAD in a single nanoplatform for tumor eradication.
Assuntos
Nanopartículas , Neoplasias , Inibidores da Angiogênese/uso terapêutico , Animais , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Dióxido de Silício/uso terapêuticoRESUMO
Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin-fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity. The co-administration of a cytotoxic payload and a protease to elicit vascular infarction in tumours with biodegradable tumour-targeted nanoparticles represents a promising strategy for improving the therapeutic index of coagulation-based tumour therapy.
Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Tratamento Farmacológico/métodos , Infarto/tratamento farmacológico , Nanopartículas/química , Trombina/administração & dosagem , Animais , Antineoplásicos/química , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Modelos Animais de Doenças , Doxorrubicina/química , Feminino , Neoplasias Hepáticas , Melanoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , Coelhos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Immunotherapy that activates the host immune system to reverse immunosuppression has emerged as a new generation of cancer treatment in both preclinical studies and clinical trials. Although immunotherapy has shown significant achievements in the treatment of various cancers, it faces challenges that limit its further evolution such as poor permeation and modest responsiveness. The development of nanoparticle drug delivery system has provided an opportunity to overcome these drawbacks and to achieve optimized immunotherapy. Based on the research of our group, we here introduce the new strategies being employed using nanoscale intelligent drug delivery systems to enhance the effects of cancer immunotherapy. We also provide a perspective on the further possible application of nanoparticles in more effective antitumor immunotherapy.