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

基本信息

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
项目类别：
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

项目摘要

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）的发展受到严重关注，限制了抗癌药物的功效，因此导致乳腺癌治疗的失败。应用表明，尽管阿霉素具有潜在的抗癌作用，但它具有剧毒，其长期应用可能引起剂量依赖性不可逆性心肌病、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。是超级有效的，如果它仍然引起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良药，因此潜力更大。使用阿霉素作为抗癌治疗药物取决于靶向递送的可用性载体，不仅可以增强对癌细胞的杀伤力，还可以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，该系统将携带和我们有将阿霉素特异性递送至化疗耐药性 Her-2+ 乳腺癌细胞中。最近报道通过P-gp下调MDR1 P-gp（ABCB1基因）的核表达特异性 siRNA 可以增加阿霉素向阿霉素耐药乳腺癌细胞的递送。然而，由于 Dox 以游离药物溶液的形式提供，而不是将其封装成颗粒对于靶向递送，它仍然对其他非癌细胞造成毒性。 siRNA 敲低多重耐药基因，如 MDR1 P-gp、MRP 或 BCRP 可能会有所帮助然而，为了使用我们实验室开发的贴有适当标记的制剂来规避 MDR，仍有一些问题需要解决（1）我们如何在药物中递送阿霉素更有针对性地针对化疗耐药乳腺癌细胞，从而使药物增强我们假设对癌细胞的细胞毒性增加，而对非癌细胞的毒性最小？无论是递送 siRNA 至沉默，靶向递送系统都是首要要求化学抗性基因或实际化学药物将杀死癌细胞而不杀死非为了解决化疗耐药性和脱靶毒性问题，需要进行靶向递送。需要开发阿霉素系统，该系统应该具有创新性、可比性和可最大限度地减少对其他非癌细胞的毒性；(2) 需要制定策略来减少对其他非癌细胞的毒性。确定靶向纳米颗粒是否在同一个纳米颗粒内同时携带阿霉素和 siRNA 颗粒或不同颗粒中以获得最佳结果，防止化学耐药性并限制脱靶我们的假设是分别递送阿霉素和 MDR 沉默 siRNA。相比之下，通过靶向纳米颗粒系统将增强细胞毒性和抗肿瘤效果该假设涉及同时递送药物和 siRNA 的靶向纳米颗粒系统。将通过两个具体目标进行测试：目标 1：靶向递送阿霉素脂质体用于 Her-2 阳性乳腺癌治疗。目标 2：评估靶向纳米颗粒是否会同时携带阿霉素和 siRNA 相同颗粒或不同颗粒中以获得最佳效果，防止化学耐药性和限制脱靶毒性。