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.

系统地服用的药物通常以非常低的浓度到达宫颈阴道（CV）。结果，影响CV道的疾病的药物疗法通常遭受效率较差和严重的不良全身副作用。通常通过全身抽象结合粘液清除机制来迅速清除在CV道（作为推注或凝胶中）局部输送的药物。这是全身化疗是宫颈癌，手术后或放射疗法的最后一个或严格同时发生的选择。目前，局部化疗不是患者的选择。为了满足对宫颈癌治疗的局部和持续药物递送的需求，我们开发了一种基于聚合物的纳米颗粒技术粘液 - 渗透颗粒（MPP），适合于局部向CV道持续递送化学治疗剂（和其他药物）。尽管常规颗粒（CP）很容易被固定在粘液的最外面的“表面”层中，这些粘液迅速从CV道中脱落，但我们发现，具有非粘合粘合剂聚合物的涂层涂层药物输送颗粒允许直径高达500 nm的颗粒快速穿透人类CV Mucus Mucus MiCus壁垒。通过穿透快速脱落的表面粘液层，我们假设MPP将避免从CV道中快速发展，（ii）获得更均匀的分布，（iii）在本地提供化学治疗剂的持续递送，从而在（IV）上显着提高针对CV肿瘤的药物效率，而（V）最小化的系统性质量。我们将准备和评估装有前线化学治疗药物的可生物降解的MPP，并测试它们以与MPP相同的颗粒，除非没有粘液int涂层。在AIM 1中，我们将制定由可生物降解的聚合物组成的MPP和细胞粘附MPP，我们已经显示的能够持续递送广泛的生物活性分子。我们将对纳米颗粒进行彻底的物理表征，包括在新鲜的，未稀释的人CV粘液中释放动力学，释放动力学和纳米颗粒扩散速度。在AIM 2中，我们将研究小鼠CV道中的保留率和分布，并对与CP相比，对从MPP和细胞粘附MPP释放的药物进行仔细的药代动力学分析。在AIM 3中，我们将在CV模型中与CP和未包膜的药物相比，评估药物加载的MPP和细胞粘附MPP的体内效率，其中肿瘤位于CV道中。