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Activating the cGAS-STING pathway of circulating tumor cell clusters (CTC clusters) represents a promising strategy to mitigate metastases. To fully exploit the potential of cholesterol-regulating agents in activating CTCs' STING levels, we developed a nanoparticle (NP) composed of metal complex lipid (MCL). This design includes MCL-miriplatin to increase NP stiffness and loads lomitapide (lomi) modulating cholesterol levels, resulting in the creation of PLTs@Pt-lipid@lomi NPs. MCL-miriplatin not only enhances lomi's eliciting efficacy on STING pathway but also increases NPs' stiffness, thus a vital factor affecting the penetration into CTC clusters to further boost lomi's ability. Demonstrated by cy5 tracking experiments, PLTs@Pt-lipid@lomi NPs quickly attach to cancer cell via platelet membrane anchorage, penetrate deep into the spheres, and reach the subcellular endoplasmic reticulum where lomi regulates cholesterol. Additionally, these NPs have been shown to track CTCs in the bloodstream, a capability not demonstrated by the free drug. PLTs@Pt-lipid@lomi NPs more efficiently activate the STING pathway and reduce CTC stemness compared to free lomi. Ultimately, PLTs@Pt-lipid@lomi NPs reduce metastasis in a post-surgery animal model. While cholesterol-regulating agents are limited in efficacy when being repositioned as immunomodulatory agents, this MCL-composing NP strategy demonstrates the potential to effectively deliver these agents to target CTC clusters.
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Superhydrophobic coatings with excellent self-cleaning performance have attracted significant concerns from researchers. Although various superhydrophobic coatings with prominent superhydrophobic properties have been fabricated, most developed coatings are still inadequate in pipeline scale inhibition applications. In this work, nano-silica (nano-SiO2) was modified by silane coupling of vinyltriethoxysilane (VETS) and 1H, 1H, 2H, 2H-perfluorooctyltriethoxysilane (PFTS) to prepare a superhydrophobic coating. Organosilicon of PFTS and VETS was grafted onto the surface of SiO2 for preparing the superhydrophobic coating with low surface energy, and the superhydrophobic coating was cured via poly(vinylidene fluoride) (PVDF). The results showed that the contact angle of the prepared silica-based superhydrophobic coating, denoted as VETS-PFTS@SiO2/PVDF, is 159.2°, exhibiting outstanding superhydrophobicity performance. Furthermore, the superhydrophobicity coating also showed satisfactory durability performance in 200 g load wear test after 50 cycles. Importantly, the superhydrophobic coating displayed promising mechanical durability, chemical stability performance, as well as maintained excellent superhydrophobic properties after being placed in water for 3 weeks, indicating the potential for long-term utilization. In the simulated scale inhibition test, it was found that the synthesized coating can also significantly decrease the deposition rate of CaCO3 and successfully enhance its scale inhibition performance.
Assuntos
Interações Hidrofóbicas e Hidrofílicas , Silanos , Dióxido de Silício , Silanos/química , Dióxido de Silício/químicaRESUMO
The malignancy of breast cancer poses a global challenge, with existing treatments often falling short of desired efficacy. Extensive research has underscored the effectiveness of targeting the metabolism of nicotinamide adenine dinucleotide (NAD), a pivotal molecule crucial for cancer cell survival and growth, as a promising anticancer strategy. Within mammalian cells, sustaining optimal NAD concentrations relies on two key enzymes, namely nicotinamide phosphoribosyltransferase (NAMPT) and poly(ADP-ribose) polymer 1 (PARP1). Recent studies have accentuated the potential benefits of combining NAMPT inhibitors and PARP1 inhibitors to enhance therapeutic outcomes, particularly in breast cancer. In this study, we designed and synthesized eleven novel NAMPT/PARP1 dual-target inhibitors. Among them, compound DDY02 exhibited acceptable inhibitory activities against both NAMPT and PARP1, with IC50 values of 0.01 and 0.05 µM, respectively. Moreover, in vitro evaluations revealed that treatment with DDY02 resulted in proliferation inhibition, NAD depletion, DNA damage, apoptosis, and migration inhibition in MDA-MB-468 cells. These results posit DDY02, by targeting NAD metabolism through inhibiting both NAMPT and PARP1, as a promising lead compound for the development of breast cancer therapy.
Assuntos
Antineoplásicos , Neoplasias da Mama , Proliferação de Células , NAD , Nicotinamida Fosforribosiltransferase , Poli(ADP-Ribose) Polimerase-1 , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Humanos , NAD/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Feminino , Proliferação de Células/efeitos dos fármacos , Linhagem Celular Tumoral , Apoptose/efeitos dos fármacos , Desenho de Fármacos , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases/química , Simulação de Acoplamento MolecularRESUMO
The oral delivery of doxorubicin (DOX), an anti-cancer drug, encounters multiple hurdles such as limited gastrointestinal permeability, P-glycoprotein-mediated efflux, brief intestinal residence, and rapid degradation. This study introduced a novel approach utilizing hyaluronic acid (HA)-grafted fatty acid monoglycerides (HGD) to encapsulate DOX, forming HGD-DOX nanoparticles, aimed at enhancing its oral bioavailability. Drug encapsulated by HGD provided several advantages, including extended drug retention in the gastrointestinal tract, controlled release kinetics, and promotion of lymphatic absorption in the intestine. Additionally, HGD-DOX nanoparticles could specifically target CD44 receptors, potentially increasing therapeutic efficacy. The uptake mechanism of HGD-DOX nanoparticles primarily involved clathrin-mediated, caveolin-mediated and macropinocytosis endocytosis. Pharmacokinetic analysis further revealed that HGD significantly prolonged the in vivo residence time of DOX. In vivo imaging and pharmacodynamic studies indicated that HGD possessed tumor-targeting capabilities and exhibited a significant inhibitory effect on tumor growth, while maintaining an acceptable safety profile. Collectively, these findings position HGD-DOX nanoparticles as a promising strategy to boost the oral bioavailability of DOX, offering a potential avenue for improved cancer treatment.
Assuntos
Doxorrubicina , Receptores de Hialuronatos , Ácido Hialurônico , Nanopartículas , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Ácido Hialurônico/química , Animais , Nanopartículas/química , Receptores de Hialuronatos/metabolismo , Humanos , Administração Oral , Camundongos , Portadores de Fármacos/química , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Breast cancer, the most prevalent malignant tumor among women globally, is significantly influenced by the Wnt/ß-catenin signaling pathway, which plays a crucial role in its initiation and progression. While conventional chemotherapy, the standard clinical treatment, suffers from significant drawbacks like severe side effects, high toxicity, and limited prognostic efficacy, Traditional Chinese Medicine (TCM) provides a promising alternative. TCM employs a multi-targeted therapeutic approach, which results in fewer side effects and offers a high potential for effective treatment. This paper presents a detailed analysis of the therapeutic impacts of TCM on various subtypes of breast cancer, focusing on its interaction with the Wnt/ß-catenin signaling pathway. Additionally, it explores the effectiveness of both monomeric and compound forms of TCM in the management of breast cancer. We also discuss the potential of establishing biomarkers for breast cancer treatment based on key proteins within the Wnt/ß-catenin signaling pathway. Our aim is to offer new insights into the prevention and treatment of breast cancer and to contribute to the standardization of TCM.
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BRD4 inhibitors have demonstrated promising potential in cancer therapy. However, their therapeutic efficacy in breast cancer varies depending on the breast cancer subtype, particularly in the treatment of TNBC. In this study, we designed and synthesized 94 derivatives of 4-(3-(3,5-dimethylisoxazol-4-yl)benzyl)phthalazin-1(2H)-one to evaluate their inhibitory activities against BRD4. Notably, compound DDT26 exhibited the most potent inhibitory effect on BRD4, with an IC50 value of 0.237 ± 0.093 µM. DDT26 demonstrated significant anti-proliferative activity against both TNBC cell lines and MCF-7 cells. Intriguingly, the phthalazinone moiety of DDT26 mimicked the PAPR1 substrate, resulting in DDT26 displaying a moderate inhibitory effect on PARP1 with an IC50 value of 4.289 ± 1.807 µM. Further, DDT26 was shown to modulate the expression of c-MYC and γ-H2AX, induce DNA damage, inhibit cell migration and colony formation, and arrest the cell cycle at the G1 phase in MCF-7 cells. Our findings present potential lead compounds for the development of potent anti-breast cancer agents targeting BRD4.