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Ultrasmall nanostructured drug based pH-sensitive liposome for effective treatment of drug-resistant tumor.

ABSTRACT: BACKGROUND:Cancer cells always develop ways to resist and evade chemotherapy. To overcome this obstacle, herein, we introduce a programmatic release drug delivery system that imparts avoiding drug efflux and nuclear transport in synchrony via a simple nanostructured drug strategy. RESULTS:The programmatic liposome-based nanostructured drugs (LNSD) contained two modules: doxorubicin (DOX) loaded into tetrahedral DNA (TD,?~?10 nm) to form small nanostructured DOX, and the nanostructured DOX was encapsulated into the pH-sensitive liposomes. In the in vitro and in vivo studies, LNSD shows multiple benefits for drug resistance tumor treatment: (1) not only enhanced the cellular DOX uptake, but also maintained DOX concentration in an optimum level in resistant tumor cells via nanostructure induced anti-efflux effect; (2) small nanostructured DOX efficiently entered into cell nuclear via size depended nuclear-transport for enhanced treatment; (3) improved the pharmacokinetics and biodistribution via reducing DOX leakage during circulation. CONCLUSIONS:The system developed in this study has the potential to provide new therapies for drug-resistant tumor.

SUBMITTER: Li Y

PROVIDER: S-EPMC6884872 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Ultrasmall nanostructured drug based pH-sensitive liposome for effective treatment of drug-resistant tumor.

Li Yanyan Y Zhai Yongxia Y Liu Wei W Zhang Kaixiang K Liu Junjie J Shi Jinjin J Zhang Zhenzhong Z

Journal of nanobiotechnology 20191129 1

<h4>Background</h4>Cancer cells always develop ways to resist and evade chemotherapy. To overcome this obstacle, herein, we introduce a programmatic release drug delivery system that imparts avoiding drug efflux and nuclear transport in synchrony via a simple nanostructured drug strategy.<h4>Results</h4>The programmatic liposome-based nanostructured drugs (LNSD) contained two modules: doxorubicin (DOX) loaded into tetrahedral DNA (TD, ~ 10 nm) to form small nanostructured DOX, and the nanostruct ...[more]

PMID: 31783863

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Project description:BACKGROUND:Melanoma is the most aggressive and deadly form of skin cancer with increasing case numbers worldwide. The development of inhibitors targeting mutated BRAF (found in around 60% of melanoma patients) has markedly improved overall survival of patients with late-stage tumors, even more so when combined with MEK inhibitors targeting the same signaling pathway. However, invariably patients become resistant to this targeted therapy resulting in rapid progression with treatment-refractory disease. The purpose of this study was the identification of new kinase inhibitors that do not lead to the development of resistance in combination with BRAF inhibitors (BRAFi), or that could be of clinical benefit as a 2nd line treatment for late-stage melanoma patients that have already developed resistance. METHODS:We have screened a 274-compound kinase inhibitor library in 3 BRAF mutant melanoma cell lines (each one sensitive or made resistant to 2 distinct BRAFi). The screening results were validated by dose-response studies and confirmed the killing efficacies of many kinase inhibitors. Two different tools were applied to investigate and quantify potential synergistic effects of drug combinations: the Chou-Talalay method and the Synergyfinder application. In order to exclude that resistance to the new treatments might occur at later time points, synergistic combinations were administered to fluorescently labelled parental and resistant cells over a period of >?10?weeks. RESULTS:Eight inhibitors targeting Wee1, Checkpoint kinase 1/2, Aurora kinase, MEK, Polo-like kinase, PI3K and Focal adhesion kinase killed melanoma cells synergistically when combined with a BRAFi. Additionally, combination of a Wee1 and Chk inhibitor showed synergistic killing effects not only on sensitive cell lines, but also on intrinsically BRAFi- and treatment induced-resistant melanoma cells. First in vivo studies confirmed these observations. Interestingly, continuous treatment with several of these drugs, alone or in combination, did not lead to emergence of resistance. CONCLUSIONS:Here, we have identified new, previously unexplored (in the framework of BRAFi resistance) inhibitors that have an effect not only on sensitive but also on BRAFi-resistant cells. These promising combinations together with the new immunotherapies could be an important step towards improved 1st and 2nd line treatments for late-stage melanoma patients.

Project description:PurposeZinc phthalocyanine (ZnPc) has been applied widely in photodynamic therapy (PDT) with high ROS-production capacity and intense absorption in the near-infrared region. However, weak tumor targeting and the aggregation tendency of ZnPc seriously affect the therapeutic effect of PDT. Therefore, overcoming the aggregation of ZnPc and enhancing its antitumor effect were the purpose of this study.MethodsIn this study, we first found that the aggregation behaviors of the photosensitizer ZnPc(TAP)4, ZnPc substituted by tertiary amine groups, were regulated finely by pH and that ZnPc(TAP)4 could be disaggregated gradually as the pH descended. ZnPc(TAP)4 and human serum albumin (HSA) molecules were assembled into nanoparticles (NPs) for tumor targeting. Meanwhile, the chemotherapy drug paclitaxel (Ptx) was loaded into HSA NPs together with ZnPc(TAP)4 for dual antitumor effects. HSA NPs loading both ZnPc(TAP)4 and Ptx (NP-ZnPc[TAP]4-Ptx) were characterized by particle size and in vitro release. Cytotoxicity, subcellular localization, tumor targeting, and anticancer effect in vivo were investigated respectively.ResultsWe found that NP-ZnPc(TAP)4-Ptx had good stability with qualifying particle size. Interestingly, ZnPc(TAP)4 was released from the NPs and the photodynamic activity enhanced in the acidic environment of tumor. In addition, NP-ZnPc(TAP)4-Ptx had prominent cytotoxicity and time-dependent subcellular localization characteristics. Through a three-dimensional animal imaging system, NP-ZnPc(TAP)4-Ptx showed much-enhanced tumor targeting in tumor-bearing mice. Above all, NP-ZnPc(TAP)4-Ptx was demonstrated to have the synergistic anticancer effect of PDT and chemotherapy.ConclusionNP-ZnPc(TAP)4-Ptx had enhanced tumor targeting for the pH-sensitive property of ZnPc(TAP)4 and the transport function of HSA. NP-ZnPc(TAP)4-Ptx possessed a double-anticancer effect through the combination of ZnPc(TAP)4 and Ptx. This drug-delivery system may also be used to carry chemotherapy drugs other than Ptx for improving antitumor effects.

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Ultrasmall nanostructured drug based pH-sensitive liposome for effective treatment of drug-resistant tumor.

Publications

Ultrasmall nanostructured drug based pH-sensitive liposome for effective treatment of drug-resistant tumor.

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