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Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma.

机译：工程化新型靶向纳米颗粒制剂，以提高常规化学疗法对多发性骨髓瘤的治疗效果。

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摘要

Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ∼7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth inhibition in vivo. Carfilzomib, another proteasome inhibitor, was embedded into the lipid bilayer of liposomes to improve its therapeutic efficacy. VLA-4 antagonist peptides were also incorporated to facilitate MM cell targeting and uptake. The liposomal carfilzomib nanoparticles demonstrated improved therapeutic index and synergy with doxorubicin compared to free carfilzomib. These nanoparticle formulations can significantly improve the efficacy of the respective therapeutic agents and have an immense potential to positively impact the treatment of MM providing for improved patient outcomes.
机译：多发性骨髓瘤（MM）是血液恶性肿瘤，是由于体内浆细胞的克隆扩增不受控制而引起的。尽管最近在医学上取得了进步，但由于耐药性的发展，该病仍基本无法治愈，中位生存期约为7年。本论文将探索纳米技术的新进展，它将小分子化学疗法的细胞毒性作用与纳米颗粒的肿瘤靶向能力相结合，以创造出新型的纳米颗粒制剂，该制剂在MM的治疗中表现出增强的治疗指数。首先，通过酸不稳定的键将阿霉素表面缀合到胶束纳米颗粒上，以增加药物在肿瘤上的积累。细胞表面受体Very Late Antigen-4（VLA-4; alpha4beta1）在造血起源的癌症上表达，并且在MM的细胞粘附介导的耐药性（CAM-DR）中起着至关重要的作用。因此，通过多方面程序将VLA-4拮抗剂肽偶联到纳米颗粒上，以主动靶向MM细胞并同时抑制CAM-DR。胶束阿霉素纳米颗粒能够克服CAM-DR并显示出相对于游离阿霉素改善的治疗指数。除阿霉素外，其他种类的治疗剂（如蛋白酶体抑制剂）也可以掺入纳米颗粒中以改善治疗效果。利用硼酸化学，使用可逆的硼酸酯键合成硼替佐米前药，然后将其掺入脂质体中。基于异丁硼酸的稳定性，筛选了可能在硼替佐米前药合成中使用的不同硼酸酯键。脂质体硼替佐米纳米粒在体外对MM细胞表现出明显的蛋白酶体抑制作用和细胞毒性，并显着降低了与游离硼替佐米相关的非特异性毒性，同时在体内维持了显着的肿瘤生长抑制作用。卡非佐米，另一种蛋白酶体抑制剂，被嵌入脂质体的脂质双层中以改善其治疗功效。还掺入了VLA-4拮抗剂肽以促进MM细胞的靶向和摄取。与游离卡非佐米相比，脂质体卡非佐米纳米颗粒具有改善的治疗指数和与阿霉素的协同作用。这些纳米颗粒制剂可以显着改善各自治疗剂的功效，并且具有积极影响MM治疗的巨大潜力，从而可以改善患者的预后。

著录项

  • 作者

    Ashley, Jonathan D.;

  • 作者单位

    University of Notre Dame.;

  • 授予单位 University of Notre Dame.;
  • 学科 Engineering Biomedical.;Nanoscience.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 172 p.
  • 总页数 172
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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