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Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance.

机译：纳米粒子介导的化学疗法和光动力疗法相结合，克服了肿瘤的耐药性。

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摘要

Tumor cells utilize multiple mechanisms to evade the cytotoxic effect of anticancer drugs. Overexpression of drug efflux transporters like P-glycoprotein (P-gp), altered tumor microenvironment, and sequestration of the drug in acidic cellular organelles are important factors that prevent the accumulation of effective cellular concentrations of anticancer drug. The hypothesis of this research is that nanoparticle-mediated combination chemotherapy and photodynamic therapy (PDT) will target multiple mechanisms of drug resistance, resulting in more effective inhibition of resistant-tumor than conventional PDT and chemotherapy. To test this hypothesis, anticancer efficacy of aerosol OT-alginate (AOT-alginate) nanoparticles loaded with a combination of doxorubicin (as a model chemotherapeutic drug) and methylene blue (as a model photosensitizer for PDT) was tested in vitro and in vivo. The objectives of the research were to (1) formulate AOT-alginate nanoparticles loaded with combination of methylene blue and doxorubicin; (2) investigate the anticancer effectiveness of nanoparticle-mediated combination therapy in vitro in drug-resistant cell lines; (3) determine the optimal treatment conditions for effective tumor growth inhibition in vivo; and (4) determine the underlying mechanisms for enhanced therapeutic efficacy. Our long-term goal is to develop an anticancer treatment modality that addresses various mechanisms of drug resistance and enables an effective therapeutic response in drug-refractory cancer.;Both doxorubicin and methylene blue could be loaded in AOT-alginate nanoparticles efficiently. Physicochemical characterization studies indicated that nanoparticles have spherical morphology and size 100 nm in diameter with a net negative surface charge. Nanoparticles were stable and easily dispersible in buffers and serum-containing cell culture medium. Previous studies in our laboratory have established the anticancer effectiveness of nanoparticles loaded with doxorubicin; however, no information was available on the suitability of AOT-alginate nanoparticles as carriers in PDT. Initial studies, therefore, investigated the in vitro PDT effectiveness of methylene blue-loaded nanoparticles. Cytotoxicity studies indicated that AOT-alginate nanoparticles significantly enhanced and sustained the PDT efficacy of methylene blue in drug-sensitive tumor cells. Mechanistic studies suggested that greater nuclear delivery of methylene blue and enhanced reactive oxygen species (ROS) production could have contributed to the enhanced PDT efficacy of nanoparticle-encapsulated methylene blue.;The use of AOT-alginate nanoparticles for the simultaneous delivery of doxorubicin and methylene blue was then investigated in drug resistant tumor cells in vitro. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis, resulting in enhanced cytotoxicity in drug-resistant tumor cells. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs following combination therapy. Further, nanoparticle-mediated combination therapy resulted in significant ROS production compared to single drug treatment. Based on the positive results from in vitro studies, further studies investigating the therapeutic benefit of nanoparticle-mediated combination therapy were carried out in vivo. Balb/c mice bearing syngeneic JC tumors were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Enhanced accumulation of both doxorubicin and methylene blue in resistant tumor cells following treatment with nanoparticles resulted in significant inhibition of tumor cell proliferation and increased induction of apoptosis. In addition, nanoparticle-mediated combination therapy resulted in tumor microvessel damage.;In conclusion, nanoparticle-mediated combination chemotherapy using doxorubicin and PDT using methylene blue resulted in multiple mechanisms of tumor growth inhibition. The results of these studies thus suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic efficacy against drug-resistant tumors.
机译：肿瘤细胞利用多种机制逃避抗癌药的细胞毒性作用。药物外排转运蛋白如P-糖蛋白（P-gp）的过表达，肿瘤微环境的改变以及在酸性细胞器中的螯合是阻止有效抗癌药物浓度升高的重要因素。这项研究的假设是，纳米粒子介导的联合化疗和光动力疗法（PDT）将针对多种耐药机制，从而比常规PDT和化学疗法更有效地抑制耐药性。为了检验该假设，在体外和体内测试了装载有阿霉素（作为模型化学治疗药物）和亚甲蓝（作为PDT的模型光敏剂）的组合的OT-藻酸盐气雾剂OT-藻酸盐纳米颗粒的抗癌功效。该研究的目的是（1）配制载有亚甲基蓝和阿霉素的AOT-藻酸盐纳米颗粒； （2）研究纳米粒子介导的联合治疗对耐药细胞株的体外抗癌作用； （3）确定有效抑制体内肿瘤生长的最佳治疗条件； （4）确定增强疗效的潜在机制。我们的长期目标是开发一种抗癌治疗方法，以解决各种耐药性机制，并在药物难治性癌症中实现有效的治疗反应。阿霉素和亚甲蓝都可以有效地负载在AOT-藻酸盐纳米颗粒中。物理化学特征研究表明，纳米颗粒具有球形形态，直径小于100 nm，带有净负表面电荷。纳米颗粒稳定并且易于分散在缓冲液和含血清的细胞培养基中。我们实验室中的先前研究已经确定了载有阿霉素的纳米颗粒的抗癌作用。但是，尚无关于AOT-藻酸盐纳米颗粒作为PDT载体的适用性的信息。因此，初步研究调查了亚甲基蓝负载纳米粒子的体外PDT有效性。细胞毒性研究表明，AOT-藻酸盐纳米颗粒在药物敏感性肿瘤细胞中显着增强并维持了亚甲基蓝的PDT效力。机理研究表明，亚甲基蓝的更大核传递和增加的活性氧（ROS）产生可能有助于增强纳米颗粒包裹的亚甲基蓝的PDT功效。;使用AOT-藻酸盐纳米颗粒同时传递阿霉素和亚甲基蓝然后在体外在耐药性肿瘤细胞中研究了蓝色。纳米粒子介导的联合治疗导致凋亡和坏死的显着诱导，导致耐药肿瘤细胞的细胞毒性增强。细胞毒性的改善可能与两种药物联合治疗后细胞内和细胞核传递的增强有关。此外，与单药治疗相比，纳米粒子介导的联合治疗导致大量的ROS产生。基于体外研究的积极结果，在体内进行了进一步研究，研究了纳米粒子介导的联合疗法的治疗益处。携带同基因JC肿瘤的Balb / c小鼠用作抗药性肿瘤模型。纳米粒子介导的联合治疗显着抑制肿瘤生长并改善动物存活率。用纳米颗粒处理后，抗药性肿瘤细胞中阿霉素和亚甲蓝的积累增强导致肿瘤细胞增殖的显着抑制和凋亡诱导的增加。此外，纳米颗粒介导的联合疗法导致肿瘤微血管损伤。总之，使用阿霉素和亚甲基蓝PDT进行的纳米颗粒介导的联合化疗导致多种肿瘤生长抑制机制。这些研究结果因此表明，使用阿霉素和亚甲基蓝的纳米粒子介导的联合化学疗法和光动力疗法对耐药性肿瘤具有显着的治疗功效。

著录项

  • 作者

    Khdair, Ayman Abed.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 228 p.
  • 总页数 228
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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