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Development and evaluation of PLGA-S S-PEG micelles coencapsulating curcumin difluorinated and paclitaxel for synergistic therapeutic efficacy.

机译：共包裹姜黄素二氟化和紫杉醇的PLGA-S S-PEG胶束的开发和评估，以产生协同治疗效果。

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摘要

Solid tumors like pancreatic tumor has unique property of forming a dense desmoplastic layer around the tumor cells making it difficult for the drug to transport across this layer. Multi drug resistance is also one of the major limitation of chemotherapy. Therefore the aim of this project was to make PLGA-SS-PEG micelles encapsulating CDF and paclitaxel for synergistic cancer therapy. CDF was found to have 16-fold better half-life when compared to curcumin maintaining equivalent bioactivity. Since CDF has chemosensitizing property we tested this by incorporating CDF and paclitaxel in same formulation and tested their synergy on BXPC3 pancreatic cancer cell line and SKOV3 ovarian cancer cell line that is paclitaxel resistant. Here we utilized a number of techniques including incorporation of PEG surface molecules thereby avoiding uptake by monophagocytic system and cysteine protease liable conjugation of PEG to the micelles making CDF and paclitaxel release specific to tumor tissue by enhanced permeation and retention effect. All the micelle formulations were below 200 nm size range. Our drug release study proved that these micelles undergo a fast sheddable process upon encountering the reduction sensitive condition like higher glutathione (GSH) levels. Cell cytotoxicity studies revealed the copolymer has good biocompatibility and self-assembled micelles showed drug loading of around 9 % for both the drugs and they released the drug quantitatively in response to the level of GSH. The synergistic effect was studied by Chou-Talalay method. There was a time and concentration dependent cell killing. Maximum synergy was observed at 72 h time point for BXPC3 cells and SKOV3 cells at 72 h time point with PLGA-S-S-PEG micelles coencapsulating both CDF and paclitaxel. The micelle formulation has higher synergy than compared to free drug combination in both cell lines at 72 hour time point. Overall IC50 values of both CDF and paclitaxel were reduced when used in combination. Based on the results of our study it indicates that these micelles have a potential promote tumor penetration because of smaller size, prolonged circulation and EPR effect and release the drug specifically in tumor cells upon exposure to highly reductive environment. Since these micelles incorporated two drugs they will be efficient for chemotherapy in multi drug resistant tumors.
机译：诸如胰腺肿瘤的实体瘤具有在肿瘤细胞周围形成致密的去增生层的独特特性，从而使药物难以穿过该层转运。多药耐药性也是化学疗法的主要限制之一。因此，该项目的目的是制造包裹CDF和紫杉醇的PLGA-SS-PEG胶束，用于协同癌症治疗。与姜黄素保持等效的生物活性相比，发现CDF的半衰期延长了16倍。由于CDF具有化学增敏特性，我们通过将CDF和紫杉醇以相同的配方掺入来进行测试，并测试了它们对紫杉醇耐药的BXPC3胰腺癌细胞系和SKOV3卵巢癌细胞系的协同作用。在这里，我们利用了包括掺入PEG表面分子在内的多种技术，从而避免了单吞噬系统的吸收以及PEG与胶束的半胱氨酸蛋白酶易结合，从而通过增强的渗透和保留效应使CDF和紫杉醇对肿瘤组织具有特异性释放。所有胶束制剂均在200nm以下的尺寸范围内。我们的药物释放研究证明，这些胶束在遇到还原敏感性条件（例如更高的谷胱甘肽（GSH）水平）时会经历快速的脱落过程。细胞细胞毒性研究表明，该共聚物具有良好的生物相容性，自组装胶束显示两种药物的载药量均约为9％，并且它们根据GSH的含量定量释放药物。通过Chou-Talalay方法研究了协同作用。存在时间和浓度依赖性的细胞杀伤作用。对于BXPC3细胞和SKOV3细胞，在72小时的时间点观察到最大协同作用，其中PLGA-S-S-PEG胶束共包封CDF和紫杉醇。与在72小时时间点的两种细胞系中的游离药物组合相比，胶束制剂具有更高的协同作用。组合使用时，CDF和紫杉醇的总体IC50值降低。根据我们的研究结果，表明这些胶束具有较小的尺寸，延长的循环和EPR效应，具有促进肿瘤渗透的潜能，并且在暴露于高度还原性环境后会在肿瘤细胞中特异性释放药物。由于这些胶束结合了两种药物，因此它们在多药耐药肿瘤中的化学疗法将是有效的。

著录项

  • 作者

    Cheemalakonda, Lakshmi Deepika.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Health Sciences Pharmacy.;Health Sciences Oncology.
  • 学位 M.S.
  • 年度 2014
  • 页码 100 p.
  • 总页数 100
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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