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Thermally Targeted Delivery of Anti-Cancer Therapeutics Using Elastin-like Polypeptide in Breast and Pancreatic Cancers.

机译：在乳腺癌和胰腺癌中使用弹性蛋白样多肽的抗癌治疗药物的热靶向递送。

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摘要

Existing therapies for the treatment of breast and pancreatic cancers usually consist of a combination of chemotherapy, surgery, and/or radiation therapy. The limitations of this type of treatment are abundant. The majority of chemotherapeutic agents used in clinics are highly toxic to both tumor cells and normal tissues due to the lack of specificity. Resistance can develop due to over-exposure of these agents. To address these issues, these agents must be made more exclusive toward the tumor site. This can be achieved by developing drugs that are toxic only to tumor cells or by developing carriers that allow the drug to be targeted to the tumor site, thereby reducing both systemic accumulation and, as a result, unwanted side effects. To achieve this goal, this work describes the development of Elastin-like Polypeptide (ELP) as a thermally responsive biopolymeric carrier to accomplish the delivery of two small molecule drugs—doxorubicin and N-butyldiacetate doxorubicin—and the therapeutic peptide p21 that inhibits the cell cycle. ELP is a macromolecule that remains soluble when injected systemically but will undergo a phase transition and accumulate in a specific site in the presence of hyperthermia. This property of ELP can be exploited for thermal targeting in the treatment of solid tumors by fusing a therapeutic to ELP to enhance the efficacy while reducing systemic toxicity. In this study, ELP was modified by the addition of a cell-penetrating peptide (CPP) to facilitate entry into the cell, increasing ELP's intracellular uptake and either maleimide derivatives of doxorubicin or the cell cycle inhibitory peptide p21. A CPP increased the association of ELP with the cell membrane by at least 1.5-fold more than without a CPP. In fluorescent imaging studies, Dox was seen in the nucleus similarly to free Dox. When SynB1-ELP-DOX0 was used in an animal model of breast cancer, SynB1-ELP-DOXO, in combination with hyperthermia, reduced tumor size significantly more than free dox in the presence or absence of heat. Using a highly potent Dox derivative (NBD), SynB1-ELP + ELP-NBD was ∼1000x more toxic to the cells than the parent compound Dox and overcame multi-drug resistance better than free NBD. Additionally, the maximum tolerated dose in the animals was 250 nmol/kg with SynB1-ELP + ELP-NBD compared to 600 nmol/kg of free NBD, a 2.4-fold difference. When comparing p21-ELP-Bac and ELP-p21, 1.6-fold more p21-ELP-Bac accumulated in the heated tumor compared to other groups two hours after injection; this accumulation was still noticeable 48 h after injection (1.3-fold). These studies validate the usefulness of a CPP in order to translocate ELP across the cellular membrane. Furthermore, these studies prove that ELP in combination with hyperthermia provides a new alternative for the treatment of solid tumors.
机译：现有的用于治疗乳腺癌和胰腺癌的疗法通常包括化学疗法，手术和/或放射疗法的组合。这种治疗方法的局限性很大。由于缺乏特异性，临床上使用的大多数化学治疗剂对肿瘤细胞和正常组织均具有高毒性。由于这些试剂的过度暴露会产生耐药性。为了解决这些问题，必须使这些药剂对肿瘤部位更具排他性。这可以通过开发仅对肿瘤细胞有毒的药物或通过开发使药物靶向肿瘤部位的载体来实现，从而既减少了全身蓄积，又减少了不良副作用。为了实现这一目标，这项工作描述了类弹性蛋白多肽（ELP）作为热响应性生物聚合物载体的开发，以完成两种小分子药物（阿霉素和N-二乙酸二丁酯阿霉素）的递送以及抑制细胞的治疗性肽p21周期。 ELP是一种大分子，当全身注射时仍然可溶，但会发生相变并在存在高热的情况下积聚在特定部位。通过将治疗剂与ELP融合以增强功效，同时降低全身毒性，可以利用ELP的这一特性来治疗实体瘤中的热靶向。在这项研究中，通过添加细胞穿透肽（CPP）来修饰ELP以促进其进入细胞，增加ELP的细胞内摄取以及阿霉素的马来酰亚胺衍生物或细胞周期抑制性肽p21。与没有CPP相比，CPP使ELP与细胞膜的缔合增加了至少1.5倍。在荧光成像研究中，在核中看到的Dox类似于游离的Dox。当在乳腺癌动物模型中使用SynB1-ELP-DOX0时，SynB1-ELP-DOXO与热疗相结合，在存在或不存在热量的情况下，肿瘤的大小明显比游离dox大得多。使用高效的Dox衍生物（NBD），SynB1-ELP + ELP-NBD对细胞的毒性比母体化合物Dox高约1000倍，并且比游离NBD更好地克服了多重耐药性。此外，与600 nmol / kg的游离NBD相比，SynB1-ELP + ELP-NBD对动物的最大耐受剂量为250 nmol / kg，相差2.4倍。当比较p21-ELP-Bac和ELP-p21时，注射后两个小时，在加热的肿瘤中积累的p21-ELP-Bac比其他组多1.6倍。注射后48小时仍很明显（1.3倍）。这些研究证实了CPP用于将ELP跨细胞膜转运的有用性。此外，这些研究证明ELP与热疗相结合为实体瘤的治疗提供了新的选择。

著录项

  • 作者

    Walker, Leslie Robinson.;

  • 作者单位

    The University of Mississippi Medical Center.;

  • 授予单位 The University of Mississippi Medical Center.;
  • 学科 Chemistry Biochemistry.;Health Sciences Oncology.;Chemistry Pharmaceutical.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 124 p.
  • 总页数 124
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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