Mucus penetrating nanoparticles for early stage cervical cancer

粘液穿透纳米粒子治疗早期宫颈癌

基本信息

批准号：
7699727
负责人：
Justin S. Hanes
金额：
$ 32.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7699727
关键词：
Abraxane Address Adhesives Adjuvant Adverse effects Affect Aftercare Albumins Animals Area Area Under Curve Binding Biocompatible Materials Biological Assay Blood Blood Circulation Body Weight decreased Bolus Infusion Caliber Cells Cervix Neoplasms Charge Chemotherapy-Oncologic Procedure Cisplatin Combination Drug Therapy Confocal Microscopy Control Groups Data Development Diffusion Disease Dose Doxorubicin Drug Delivery Systems Drug Formulations Drug Kinetics Electron Microscopy Encapsulated Engineering Epithelial Cells Epithelium Ethylene Glycols Female Fluorescence Folate Gel Glycolic-Lactic Acid Polyester Human Image Implant In Vitro Infertility Kinetics Label Latex Latex Particles Life Ligands Luciferases Malignant Neoplasms Malignant neoplasm of cervix uteri Measurement Measures Medical Methods Microscopy Molecular Weight Monitor Morphology Mucous Membrane Mucous body substance Mus Nanotechnology Nature Newsletter Operative Surgical Procedures Organ Paclitaxel Pain Patients Pharmaceutical Preparations Pharmacotherapy Polymers Procedures Property Proteins Radiation therapy Radio Radiosurgery Resolution Signal Transduction Spatial Distribution Speed Staging Surface System Technology Testing Thick Time Tissues Toxic effect Treatment Protocols Tumor Tissue Vagina absorption base biocompatible polymer biodegradable polymer cancer cell cancer therapy chemotherapy density di-block copolymer drug efficacy drug testing ethylene glycol fluorescence imaging improved in vivo light scattering luminescence mouse model nanoparticle neoplastic cell new technology particle receptor reproductive sebacic acid tumor tumor growth

项目摘要

Drugs administered systemically typically reach the cervicovaginal (CV) tract in very low concentrations. As a result, drug therapies for diseases that affect the CV tract typically suffer from poor efficacy and significant adverse systemic side effects. Drugs delivered locally in the CV tract (as a bolus or in gels) are typically cleared rapidly by systemic absorption combined with mucus clearance mechanisms. Thus, systemic chemotherapy is the last or strictly concurrent option for cervical cancer, after surgery or together with radiotherapy; local chemotherapy is not currently an option for patients. To address the need for localized and sustained drug delivery for cervical cancer therapy, we have developed mucus-penetrating particles (MPP), a polymer-based nanoparticle technology suitable for sustained delivery of chemotherapeutics (and other drugs) locally to the CV tract. While conventional particles (CP) are easily immobilized in the outermost “surface” layers of mucus that are shed rapidly out of the CV tract, we discovered that coating drug delivery particles with non-mucoadhesive polymers allows particles as large as 500 nm in diameter to rapidly penetrate human CV mucus barriers. By penetrating the rapidly shed surface mucus layer, we hypothesize that MPP will: (i) avoid rapid elimination from the CV tract, (ii) achieve more uniform distribution, and (iii) provide sustained delivery of chemotherapeutics locally and, thereby, (iv) significantly improve drug efficacy against CV tumors while (v) minimizing systemic toxicity. We will prepare and evaluate biodegradable MPP loaded with frontline chemotherapeutic drugs, and test them against particles that are in all ways identical to the MPP, except without muco-inert coatings. In Aim 1, we will formulate MPP and cell-adhesive MPP composed of biodegradable polymers that we have shown are capable of sustained delivery of a wide range of bioactive molecules. We will perform thorough physicochemical characterization of the nanoparticles, including drug loading, release kinetics and nanoparticle diffusion speeds in fresh, undiluted human CV mucus. In Aim 2, we will investigate retention and distribution in the CV tract of mice, and perform careful pharmacokinetic analysis of drugs released from MPP and cell-adhesive MPP as compared to CP. In Aim 3, we will evaluate the in vivo efficacy of drug-loaded MPP and cell-adhesive MPP compared to CP and unencapsulated drug in a mouse model where tumor is localized in the CV tract.

全身性影响的药物通常以非常低的浓度到达宫颈阴道 (CV) 道，因此，针对 CV 道疾病的药物治疗通常疗效不佳，并且在 CV 道局部输送药物会产生显着的不良全身副作用。推注剂或凝胶剂）通常通过全身吸收结合粘液清除机制而快速清除，因此，全身化疗是宫颈癌的最后或严格同步的选择，目前对于患者来说，在手术后或与局部化疗一起不是一种选择。。到为了满足宫颈癌治疗中局部持续药物输送的需求，我们开发了粘液穿透颗粒 (MPP)，这是一种基于聚合物的纳米颗粒技术，适用于将化疗药物（和其他药物）局部持续输送到心血管道。颗粒（CP）很容易固定在粘液的最外层“表面”层中，这些粘液迅速从CV道中脱落，我们发现用非粘膜粘附聚合物涂覆药物输送颗粒可以使颗粒大至直径为 500 nm，可快速穿透人类 CV 粘液屏障通过穿透快速脱落的表面粘液层，我们认为 MPP 将：(i) 避免从 CV 道快速消除，(ii) 实现更均匀的分布，以及 (iii)提供持续的局部化疗药物递送，从而 (iv) 显着提高针对 CV 肿瘤的药物疗效，同时 (v) 最大限度地减少全身毒性。我们将制备和评估负载一线化疗药物的可生物降解 MPP，并针对颗粒进行测试。除了没有粘液惰性涂层外，它们在所有方面都与 MPP 相同。在目标 1 中，我们将配制由可生物降解聚合物组成的 MPP 和细胞粘附 MPP，我们已证明它们能够持续输送多种生物活性分子。在目标 2 中，我们将对纳米粒子进行彻底的物理化学表征，包括药物负载、释放动力学和纳米粒子在新鲜、未稀释的人类 CV 粘液中的扩散速度。我们将研究小鼠 CV 道中的滞留和分布，并对 MPP 和细胞粘附 MPP 释放的药物与 CP 进行比较进行仔细的药代动力学分析。在目标 3 中，我们将评估载药 MPP 和细胞粘附 MPP 的体内功效。在肿瘤位于CV管的小鼠模型中，细胞粘附MPP与CP和未封装药物的比较。