Formulation of a targeted nanoparticle system for the treatment of chemoresistant breast cancer

用于治疗化疗耐药乳腺癌的靶向纳米颗粒系统的配制

• 批准号: 10206855
• 负责人: ANUP KUMER KUNDU
• 金额: $ 11.1万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10206855
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Address; Alpha Particles; Antineoplastic Agents; Aptamer Technology; Binding; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer therapy; Bypass; Cardiomyopathies; Cardiotoxicity; Cells; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical Research; DNA; Deposition; Development; Disease; Disseminated Malignant Neoplasm; Dose; Doxorubicin; Drug resistance; Encapsulated; Failure; Formulation; Genes; Goals; Label; Lipids; Liposomal Doxorubicin; Liposomes; Molecular Conformation; Multi-Drug Resistance; Multidrug Resistance Gene; Nanotechnology; Normal Cell; Normal tissue morphology; Nuclear; Oligonucleotides; Outcome; Pharmaceutical Preparations; Polymers; Proteins; RNA; RNA Interference; Reporting; Resistance; Resistance development; Small Interfering RNA; Specificity; Structure; System; Testing; Tissues; Toxic effect; Treatment Failure; anti-cancer; anti-cancer therapeutic; antitumor effect; aptamer; base; cancer cell; cancer drug resistance; cancer therapy; clinical application; cytotoxicity; innovation; knock-down; liver injury; malignant breast neoplasm; nanocarrier; nanoparticle; nanoparticle delivery; neoplastic cell; overexpression; particle; prevent; receptor; siRNA delivery; side effect; targeted delivery; uptake

ABSTRACT The development of multidrug resistance (MDR) in cancer cells is of grave concern, limiting the efficacy of anticancer agents and, hence, the failure of breast cancer therapy. Clinical research and application revealed that in spite of its potential anticancer effects, doxorubicin is highly toxic, and its long-term application may cause dose-dependent irreversible cardiomyopathy, severe cardiac toxicity, or liver damage, thereby limiting its application in breast cancer treatment. Even if the drug is super-efficient, if it still causes off-target toxicity and damages non-cancerous cells and tissues, the drug wouldn’t be a great remedy to treat that particular disease. As such, the greater potential of using doxorubicin as anticancer therapeutic depends on the availability of a targeted delivery vehicle, which will not only enhance the killing of cancer cells but also minimize the off-target toxicity to non-cancerous cells. The goal of this study is to enhance the delivery of doxorubicin by formulating an aptamer-labeled liposomal nanoparticle delivery system that will carry and deliver doxorubicin specifically into chemoresistant Her-2+ breast cancer cells. We have recently reported that down regulating nuclear expression of MDR1 P-gp (ABCB1 gene) by P-gp specific siRNA could increase the delivery of doxorubicin to doxorubicin resistant breast cancer cells. However, since the Dox was delivered as a free drug solution without encapsulating it into a particle for targeted delivery, it still caused toxicity to other non-cancerous cells. The targeted delivery of siRNA to knockdown multi-drug resistant genes such as MDR1 P-gp, MRP or BCRP might be helpful to circumvent MDR using the apt-labeled formulations that we have developed in our lab, however, there are some questions that still need to be addressed (1) how can we deliver doxorubicin in a more targeted fashion to the chemoresistant breast cancer cells so that the drug-enhanced cytotoxicity to cancer cells increases with a minimal toxicity to the non-cancerous cells? We assume that a targeted delivery system is an utmost requirement whether it is delivering siRNA to silence chemoresistant genes or an actual chemodrug which will kill cancer cells without killing non- cancerous cells. To address the chemoresistance as well as off-target toxicity, a targeted delivery system for doxorubicin needs to be developed which should be innovative, comparable and can minimize the toxicity to other non-cancerous cells. And (2) a strategy needs to be in place to determine whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same particles or in different particles to get the best results preventing chemoresistance and limiting off- target toxicity. Our hypothesis is that delivering doxorubicin and MDR-silencing siRNAs separately by targeted nanoparticle system will enhance the cellular toxicity and antitumor effects as compared to a targeted nanoparticle system that delivers the drug and siRNA simultaneously. This hypothesis will be tested through two specific aims: Aim 1: Targeted delivery of doxorubicin liposomes for Her-2 positive breast cancer treatment. Aim 2: Assess whether the targeted nanoparticles will carry both doxorubicin and siRNA within the same particles or in different particles to get the best results preventing chemoresistance and limiting off-target toxicity.

摘要 癌细胞中多药耐药性（MDR）的发展受到严重关注，限制了肿瘤的治疗。 抗癌剂的功效，并因此导致乳腺癌治疗的失败。临床研究和 应用显示，尽管多柔比星具有潜在的抗癌作用，但其毒性很高， 长期应用可能会导致剂量依赖性不可逆心肌病、严重心脏病 毒性或肝损伤，从而限制了其在乳腺癌治疗中的应用。即使药物 是超高效的，如果它仍然会引起脱靶毒性并损害非癌细胞和组织， 这种药物并不是治疗这种疾病的好方法。因此，更大的潜力 使用多柔比星作为抗癌治疗剂取决于靶向递送的可用性 载体，这不仅将增强对癌细胞的杀伤，而且还将最大限度地减少脱靶 对非癌细胞的毒性。本研究的目的是增强阿霉素的递送 通过配制适体标记的脂质体纳米颗粒递送系统， 将多柔比星特异性地递送到化学抗性Her-2+乳腺癌细胞中。我们有 最近报道，P-gp下调MDR 1 P-gp（ABCB 1基因）的核表达， 特异性siRNA可以增加阿霉素向阿霉素抗性乳腺癌细胞的递送。 然而，由于Dox是作为游离药物溶液递送的，而没有将其包封到颗粒中， 对于靶向递送，它仍然对其他非癌细胞产生毒性。的靶向递送 siRNA敲除MDR 1、P-gp、MRP或BCRP等多药耐药基因可能有帮助 然而，为了使用我们在实验室开发的apt标记的制剂来规避MDR， 但仍有一些问题需要解决：（1）我们如何能够在 更有针对性的方式对化疗耐药乳腺癌细胞，使药物增强 对癌细胞的细胞毒性增加，而对非癌细胞的毒性最小？我们假设 靶向递送系统是最高要求， 化疗耐药基因或实际的化疗药物，将杀死癌细胞，而不杀死非癌细胞。 癌细胞为了解决化学抗性以及脱靶毒性，靶向递送 需要开发一种用于阿霉素的系统，该系统应该是创新的、可比较的并且可以 最大限度地减少对其他非癌细胞的毒性。（2）需要制定一项战略， 确定靶向纳米颗粒是否将在相同的靶向纳米颗粒内携带阿霉素和siRNA两者， 颗粒或在不同的颗粒中，以获得最佳的结果，防止化学抗性和限制关闭- 目标毒性。我们的假设是分别递送阿霉素和MDR沉默siRNA， 通过靶向纳米颗粒系统将增强细胞毒性和抗肿瘤作用， 涉及同时递送药物和siRNA的靶向纳米颗粒系统。这一假设 将通过两个具体目标进行测试： 目的1：阿霉素脂质体靶向给药治疗Her-2阳性乳腺癌。 目的2：评估靶向纳米颗粒是否将在靶向纳米颗粒内携带多柔比星和siRNA。 相同颗粒或不同颗粒中以获得最佳结果， 脱靶毒性