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1.
J Control Release ; 371: 371-385, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38849089

RESUMO

The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.


Assuntos
Acroleína , Camptotecina , Sistemas de Liberação de Medicamentos , Nanopartículas , Neoplasias de Mama Triplo Negativas , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Humanos , Feminino , Linhagem Celular Tumoral , Acroleína/análogos & derivados , Acroleína/administração & dosagem , Acroleína/química , Camptotecina/análogos & derivados , Camptotecina/administração & dosagem , Camptotecina/uso terapêutico , Camptotecina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Ácido Linoleico/química , Ácido Linoleico/administração & dosagem , Triazóis/administração & dosagem , Triazóis/farmacologia , Triazóis/química , Dano ao DNA/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Camundongos Nus , Camundongos , Proteínas de Ciclo Celular/metabolismo , Fatores de Transcrição/metabolismo , Inibidores da Topoisomerase I/administração & dosagem , Proteínas que Contêm Bromodomínio , Azepinas
2.
J Control Release ; 370: 168-181, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38643936

RESUMO

The high prevalence and severity of hepatocellular carcinoma (HCC) present a significant menace to human health. Despite the significant advancements in nanotechnology-driven antineoplastic agents, there remains a conspicuous gap in the development of targeted chemotherapeutic agents specifically designed for HCC. Consequently, there is an urgent need to explore potent drug delivery systems for effective HCC treatment. Here we have exploited the interplay between HCC and adipocyte to engineer a hybrid adipocyte-derived exosome platform, serving as a versatile vehicle to specifically target HCC and exsert potent antitumor effect. A lipid-like prodrug of docetaxel (DSTG) with a reactive oxygen species (ROS)-cleavable linker, and a lipid-conjugated photosensitizer (PPLA), spontaneously co-assemble into nanoparticles, functioning as the lipid cores of the hybrid exosomes (HEMPs and NEMPs). These nanoparticles are further encapsuled within adipocyte-derived exosome membranes, enhancing their affinity towards HCC cancer cells. As such, cancer cell uptakes of hybrid exosomes are increased up to 5.73-fold compared to lipid core nanoparticles. Our in vitro and in vivo experiments have demonstrated that HEMPs not only enhance the bioactivity of the prodrug and extend its circulation in the bloodstream but also effectively inhibit tumor growth by selectively targeting hepatocellular carcinoma tumor cells. Self-facilitated synergistic drug release subsequently promoting antitumor efficacy, inducing significant inhibition of tumor growth with minimal side effects. Our findings herald a promising direction for the development of targeted HCC therapeutics.


Assuntos
Adipócitos , Antineoplásicos , Carcinoma Hepatocelular , Docetaxel , Exossomos , Neoplasias Hepáticas , Nanopartículas , Exossomos/metabolismo , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Animais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Humanos , Docetaxel/administração & dosagem , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Adipócitos/efeitos dos fármacos , Nanopartículas/química , Nanopartículas/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/uso terapêutico , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/farmacologia , Camundongos Nus , Fototerapia/métodos , Sistemas de Liberação de Medicamentos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Camundongos Endogâmicos BALB C
3.
Nat Commun ; 14(1): 6748, 2023 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-37875481

RESUMO

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.


Assuntos
Vacinas Anticâncer , Neoplasias , Humanos , Interleucina-15 , Biomimética , Citocinas , Imunoterapia , Receptores de Interleucina-15 , Neoplasias/terapia , Células Dendríticas
4.
J Control Release ; 361: 819-846, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37597809

RESUMO

Owing to the unique DNA damaging cytotoxicity, platinum (Pt)-based chemotherapy has long been the first-line choice for clinical oncology. Unfortunately, Pt drugs are restricted by the severe dose-dependent toxicity and drug resistance. Correspondingly, Pt(IV) prodrugs are developed with the aim to improve the antitumor performance of Pt drugs. However, as "free" molecules, Pt(IV) prodrugs are still subject to unsatisfactory in vivo destiny and antitumor efficacy. Recently, Pt(IV) prodrug nanotherapeutics, inheriting both the merits of Pt(IV) prodrugs and nanotherapeutics, have emerged and demonstrated the promise to address the underexploited dilemma of Pt-based cancer therapy. Herein, we summarize the latest fronts of emerging Pt(IV) prodrug nanotherapeutics. First, the basic outlines of Pt(IV) prodrug nanotherapeutics are overviewed. Afterwards, how versatile Pt(IV) prodrug nanotherapeutics overcome the multiple biological barriers of antitumor drug delivery is introduced in detail. Moreover, advanced combination therapies based on multimodal Pt(IV) prodrug nanotherapeutics are discussed with special emphasis on the synergistic mechanisms. Finally, prospects and challenges of Pt(IV) prodrug nanotherapeutics for future clinical translation are spotlighted.


Assuntos
Neoplasias , Pró-Fármacos , Humanos , Pró-Fármacos/uso terapêutico , Neoplasias/tratamento farmacológico , Terapia Combinada , Sistemas de Liberação de Medicamentos , Oncologia , Platina/uso terapêutico
5.
J Nanobiotechnology ; 20(1): 338, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35858898

RESUMO

Despite explosive growth in the development of nano-drug delivery systems (NDDS) targeting tumors in the last few decades, clinical translation rates are low owing to the lack of efficient models for evaluating and predicting responses. Microfluidics-based tumor-on-a-chip (TOC) systems provide a promising approach to address these challenges. The integrated engineered platforms can recapitulate complex in vivo tumor features at a microscale level, such as the tumor microenvironment, three-dimensional tissue structure, and dynamic culture conditions, thus improving the correlation between results derived from preclinical and clinical trials in evaluating anticancer nanomedicines. The specific focus of this review is to describe recent advances in TOCs for the evaluation of nanomedicine, categorized into six sections based on the drug delivery process: circulation behavior after infusion, endothelial and matrix barriers, tumor uptake, therapeutic efficacy, safety, and resistance. We also discuss current issues and future directions for an end-use perspective of TOCs.


Assuntos
Sistemas de Liberação de Fármacos por Nanopartículas , Neoplasias , Humanos , Dispositivos Lab-On-A-Chip , Microfluídica , Nanomedicina , Neoplasias/tratamento farmacológico , Microambiente Tumoral
6.
J Med Chem ; 64(21): 15936-15948, 2021 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-34723524

RESUMO

Off-target drug release and insufficient drug delivery are the main obstacles for effective anticancer chemotherapy. Prodrug-based self-assembled nanoparticles bioactivated under tumor-specific conditions are one of the effective strategies to achieve on-demand drug release and effective tumor accumulation. Herein, stimuli-activable prodrugs are designed yielding smart tumor delivery by combination of the triglyceride-mimic (TG-mimetic) prodrug structure and disulfide bond. Surprisingly, these prodrugs can self-assemble into uniform nanoparticles (NPs) with a high drug loading (over 40%) and accumulate in tumor sites specifically. The super hydrophobic TG structure can act as a gate that senses lipase to selectively control over NP dissociation and affect the glutathione-triggered prodrug activation. In addition, the impacts of the double bonds in the prodrug NPs on parent drug release and the following cytotoxicity, pharmacokinetics, and antitumor efficiency are further demonstrated. Our findings highlight the promising potential of TG-mimetic structure-gated prodrug nanoparticles for tumor-specific drug delivery.


Assuntos
Antineoplásicos/uso terapêutico , Mimetismo Molecular , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Triglicerídeos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Portadores de Fármacos , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Nanopartículas/uso terapêutico , Pró-Fármacos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Adv Healthc Mater ; 10(23): e2101407, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34601824

RESUMO

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.


Assuntos
Antineoplásicos , Nanopartículas , Pró-Fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanomedicina , Pró-Fármacos/farmacologia
8.
Asian J Pharm Sci ; 15(4): 482-491, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32952671

RESUMO

The therapeutic efficiency of active targeting nanoparticulate drug delivery systems (nano-DDS) is highly compromised by the plasma proteins adsorption on nanoparticles (NPs) surface, which significantly hinders cell membrane receptors to recognize the designed ligands, and provokes the off-target toxicity and rapid clearance of NPs in vivo. Herein, we report a novel dihydroartemisinin (DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E (apoE) on the NPs surface. The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA (PPD) NPs circulation capability in blood, facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention (EPR) effect and low-density lipoprotein receptor (LDLr)-mediated target transport, and ultimately improve the in vivo antitumor activity. Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.

9.
Biomaterials ; 217: 119279, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31252242

RESUMO

Tumor metastases account for about 90% of cancer-related death, among which lymphatic metastases play a pivotal role. Therefore, high-efficiency sentinel lymph node (SLN) identification is significant for lymph node (LN) metastasis diagnosis in clinic. Herein, a novel in vivo covalent albumin-binding near-infrared (NIR) fluorescent IR820-maleimide conjugate (IR-Mal) is firstly designed as a SLN dual-mode imaging agent. The IR-Mal conjugate exhibits bright blue appearance and its large Stokes shift (over 100 nm) increases the fluorescent imaging resolution effectively. The fluorescence intensity of covalent albumin-binding IR-Mal (BSA-IR-Mal) complex is considerably stronger than that of IR-Mal. In vivo, IR-Mal could rapidly covalently bind the tissue interstitial albumin following subcutaneous administration and BSA-IR-Mal complexes could specifically accumulate on LN, and detect both normal and metastatic SLN through naked-eye and fluorescence imaging with high resolution. Moreover, the light stability and enhanced fluorescence intensity of BSA-IR-Mal complex facilitates its diagnosis accuracy. These findings suggest that such in vivo irreversible albumin-binding fluorescence conjugates could serve as a new agent for dual-mode imaging and have a great potential to be applied in the SLNs imaging and diagnosis.


Assuntos
Verde de Indocianina/análogos & derivados , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/diagnóstico , Imagem Óptica , Soroalbumina Bovina/metabolismo , Animais , Morte Celular , Linhagem Celular Tumoral , Modelos Animais de Doenças , Endocitose , Feminino , Verde de Indocianina/síntese química , Verde de Indocianina/química , Verde de Indocianina/toxicidade , Cinética , Maleimidas/síntese química , Maleimidas/química , Maleimidas/toxicidade , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Células NIH 3T3 , Ligação Proteica
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