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: 10643871
• 负责人: ANUP KUMER KUNDU
• 金额: $ 11.25万
• 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/10643871
• 关键词: ABCB1 gene; ABCC1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Acids; Address; 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; 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; System; Testing; Therapeutic; Tissues; Toxic effect; Treatment Failure; anti-cancer; anti-cancer therapeutic; antitumor effect; aptamer; cancer cell; cancer drug resistance; cancer therapy; clinical application; cytotoxicity; delivery vehicle; innovation; knock-down; lipid nanoparticle; liver injury; malignant breast neoplasm; nanocarrier; nanoparticle; nanoparticle delivery; neoplastic cell; overexpression; particle; prevent; receptor; resistance gene; 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.

抽象的 癌细胞中多药耐药性（MDR）的发展是严重关注的，限制了 抗癌药的功效，因此，乳腺癌治疗的失败。临床研究和 应用显示，尽管具有潜在的抗癌作用，阿霉素是剧毒的，它的 长期应用可能导致剂量依赖性不可逆心肌病，严重心脏 毒性或肝脏损害，从而限制其在乳腺癌治疗中的应用。即使药物 高效，如果仍然引起靶向脱靶毒性并损害非癌细胞和组织， 该药物并不是治疗该特定疾病的好方法。因此，更大的潜力 用阿霉素作为抗癌治疗的方法取决于目标递送的可用性 车辆，这不仅会增强癌细胞的杀戮，而且还可以最大程度地减少脱靶 对非癌细胞的毒性。这项研究的目的是增强阿霉素的递送 通过制定将携带和 将阿霉素专门输送到化学耐药性HER-2+乳腺癌细胞中。我们有 最近报道，P-gp下调了MDR1 P-gp（ABCB1基因）的核表达 特异性siRNA可能会增加阿霉素向阿霉素耐药性乳腺癌细胞的递送。 但是，由于DOX是作为免费的药物溶液传递的，而无需封装成粒子 对于有针对性的递送，它仍然引起对其他非癌细胞的毒性。有针对性的交付 siRNA敲除多药抗性基因，例如MDR1 P-gp，MRP或BCRP可能有帮助 但是，要使用我们在实验室中开发的贴标签的公式来绕过MDR 仍然需要解决一些问题（1）我们如何在 对化学抗性乳腺癌细胞的更具针对性的方式，以使药物增强 对癌细胞的细胞毒性随着对非癌细胞的最小毒性而增加？我们假设 是否正在递送siRNA沉默的目标交付系统是最大的要求 化学抗性基因或实际的化学果会杀死癌细胞而不会杀死非非 - 癌细胞。为了解决化学耐药性和脱靶毒性，有针对性的递送 阿霉素的系统需要开发，这应该具有创新，可比性并且可以 最小化对其他非癌细胞的毒性。 （2）必须制定策略 确定靶向纳米颗粒是否在同一中同时携带阿霉素和siRNA 颗粒或不同颗粒中的最佳效果，以防止化学抗性和限制 - 靶毒性。我们的假设是分别递送阿霉素和MDR-SiLencing siRNA 通过有针对性的纳米颗粒系统将增强细胞毒性和抗肿瘤作用。 简单地提供药物和siRNA的靶向纳米颗粒系统。这个假设 将通过两个具体目标进行测试： 目标1：针对HER-2阳性乳腺癌治疗的阿霉素脂质体的目标递送。 AIM 2：评估目标纳米颗粒是否会在 相同的颗粒或不同颗粒中的颗粒以获得最佳的结果，以防止化学抗性和限制 脱靶毒性。