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: 10472537
• 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/10472537
• 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; 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; 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; 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