A Targeted Nanomedicine Prototype Against Enzalutamide-resistant Prostate Cancer

针对恩杂鲁胺耐药性前列腺癌的靶向纳米药物原型

基本信息

批准号：
10464889
负责人：
WADIH ARAP
金额：
$ 62.95万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464889
关键词：
3-Dimensional Affect Antibodies Antineoplastic Agents Area Binding Biodistribution Biological Markers Blood Circulation Cancer Patient Cells Chelating Agents Chemistry Clinical Trials Complex Confocal Microscopy Data Analyses Development Diagnosis Diffusion Disease Disease Progression Dose Doxorubicin Drug Delivery Systems Drug Kinetics Drug Stability Drug resistance Encapsulated Endocytosis Engineering Environment Equation Fluorescent Dyes Formulation Generations Growth Histology Human Hybrids Image Immunohistochemistry In Vitro Individual LNCaP Label Ligands Lipid Bilayers Liposomes Malignant neoplasm of prostate Mammary Neoplasms Mathematics Metastatic Prostate Cancer Methods Modeling Modification Molecular Molecular Profiling Nucleic Acids Paper Patients Pharmaceutical Preparations Phenotype Physiological Polyethylene Glycols Property Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Publishing Radio Reaction Recombinants Research Resistance Resistance development Resolution Safety Shapes Silicon Dioxide Site Small Interfering RNA Solid Neoplasm Solubility Specificity Structure-Activity Relationship Surface Technology Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Translations Transmission Electron Microscopy Treatment Efficacy Treatment Protocols Treatment outcome Treatment-related toxicity Tumor Markers Tumor Suppressor Proteins Untranslated RNA Validation Variant Work Xenograft procedure acquired drug resistance androgen deprivation therapy base biomaterial compatibility cancer therapy circulating leukemia cell clinical application cytotoxic design enzalutamide field study glucose-regulated proteins improved in vivo insight interest lead candidate light scattering mathematical model multi-scale modeling nano nanocarrier nanomedicine nanoparticle nanoparticle delivery nanoparticle drug nanotechnology platform neoplastic cell next generation novel overexpression particle precision medicine predictive modeling prevent prostate cancer cell prototype rational design real-time images resistance mechanism screening single photon emission computed tomography standard of care targeted delivery targeted treatment therapeutic nanoparticles therapy outcome trafficking tumor tumor growth tumor xenograft

项目摘要

ABSTRACT Eight percent of patients diagnosed with prostate cancer progress to lethal metastatic disease. Development of resistance to androgen-deprivation therapy and eventually, to last line chemotherapeutics such as enzalutamide (ENZ), contribute to lethal, metastatic prostate cancer. While interest to identify tumor-specific molecular signatures, termed precision medicine, is gaining popular favor, it requires identification of physiologically accessible targets. By diverting the function of a molecular tumor target by conventional anti- cancer drugs, rates of tumor growth are expected to decrease; however, this does not take into account acquired drug resistance mechanisms which are dependent on systemic drug stability, solubility or toxicity. One method to stabilize poorly soluble and/or highly toxic drugs, and potentially overcome resistance, is to encapsulate drugs in nanoparticles (NPs) to prevent their degradation and enhance their circulation time. Moreover, accumulation of loaded NPs at the tumor site can be improved by adding tumor-specific targeting moieties that induce NP endocytosis, thereby improving the therapeutic index while minimizing collateral damage to healthy cells. A prostate tumor-specific biomarker, the 78 kDa glucose-regulated protein (GRP78), was identified by the Pasqualini and Arap team by screening antibodies from prostate cancer patient sera. GRP78 is a biomarker of disease progression and, crucial to our proposed research, we recently identified human recombinant anti-GRP78 antibodies with optimal in vivo tumor targeting. In this proposal, our objective is to generate GRP78-targeted NPs against ENZ-resistant prostate cancer. We will employ the novel, modular “protocell” platform developed by the Brinker team. Protocells consist of a porous silica core, which can be engineered to accommodate varied and combination cargos, encapsulated within a supported lipid bilayer that protects and retains the cargo, and provides a biocompatible surface for conjugation to targeting and/or trafficking ligands. The Brinker team demonstrated exceptional stability of targeted, first-generation protocells in vivo with specific binding and cargo delivery to individual circulating leukemia cells. Instead of delivering chemotherapeutic drugs that work at the protein level, we propose to deliver small interfering RNAs (siRNAs) directed against the long non-coding RNA, PCA3. We showed that interfering with PCA3 inhibits growth of human prostate xenografts. Guided by predictive modeling conducted by the Cristini team, our modular GRP78-targeted protocells will be designed to package PCA3 siRNAs to selectively bind to GRP78-expressing prostate cancer cells, and deliver PCA3 siRNAs intracellularly to inhibit tumor growth. Our project is a first-in- field study that galvanizes our current combined expertise and technology. The dual prostate tumor “centric” feature of these next generation NP prototype platforms increases their specificity and efficacy, and overcomes the limitation of conventional standard-of-care drugs, particularly in the case of acquired drug resistance.

抽象的百分之八被诊断患有前列腺癌的患者进展为致命的转移性疾病。对雄激素剥夺疗法的耐药性，并最终对最后一线化疗药物产生耐药性，例如恩杂鲁胺（ENZ）有助于致命的转移性前列腺癌，同时有兴趣识别肿瘤特异性。分子特征，称为精准医学，正在赢得大众的青睐，它需要识别通过常规抗肿瘤药物转移分子肿瘤靶点的功能。癌症，肿瘤生长药物的比率预计会下降；然而，这并未考虑在内；获得性耐药机制取决于全身药物稳定性、溶解度或毒性。稳定难溶性和/或剧毒药物并潜在克服耐药性的一种方法是将药物封装在纳米粒子 (NP) 中，以防止其降解并延长其循环时间。此外，通过添加肿瘤特异性靶向可以改善负载纳米粒子在肿瘤部位的积累诱导 NP 内吞作用的部分，从而提高治疗指数，同时最大限度地减少附带对健康细胞的损害。前列腺肿瘤特异性生物标志物，78 kDa 葡萄糖调节蛋白 (GRP78)，是 Pasqualini 和 Arap 团队通过筛选前列腺癌患者血清中的抗体而发现的。 GRP78 是疾病进展的生物标志物，对我们拟议的研究至关重要，我们最近发现具有最佳体内肿瘤靶向性的人重组抗 GRP78 抗体在本提案中是我们的目标。我们将采用新型模块化纳米颗粒来生成针对 ENZ 耐药性前列腺癌的 GRP78 靶向纳米颗粒。 Brinker 团队开发的“protocell”平台由多孔二氧化硅核心组成。设计用于容纳各种组合货物，封装在支持的脂质双层内保护和保留货物，并提供生物相容性表面，用于接合目标和/或 Brinker 团队展示了靶向第一代原始细胞的卓越稳定性。体内与单个循环白血病细胞进行特异性结合和货物递送。在蛋白质水平发挥作用的化疗药物，我们建议提供小干扰 RNA (siRNA) 针对长非编码 RNA PCA3，我们发现干扰 PCA3 会抑制细胞的生长。人类前列腺异种移植物由 Cristini 团队进行的预测模型指导，我们的模块化。靶向 GRP78 的原始细胞将被设计为包装 PCA3 siRNA，以选择性结合表达 GRP78 的细胞前列腺癌细胞，并在细胞内递送 PCA3 siRNA 以抑制肿瘤生长。现场研究激发了我们当前的综合专业知识和技术“以双前列腺肿瘤为中心”。这些下一代 NP 原型平台的特点提高了它们的特异性和功效，并克服了传统标准治疗药物的局限性，特别是在获得性耐药的情况下。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Are nearly free silanols a unifying structural determinant of silica particle toxicity?

几乎游离的硅烷醇是二氧化硅颗粒毒性的统一结构决定因素吗？

DOI：
发表时间：
2020-12-01
期刊：
影响因子：
11.1
作者：
Brinker, C Jeffrey;Butler, Kimberly S;Garofalini, Stephen H
通讯作者：
Garofalini, Stephen H

Robust and Long-Term Cellular Protein and Enzymatic Activity Preservation in Biomineralized Mammalian Cells.

生物矿化哺乳动物细胞中稳健且长期的细胞蛋白和酶活性保存。

DOI：
10.1021/acsnano.1c08103
发表时间：
2022-02-10
期刊：
ACS nano
影响因子：
17.1
作者：
Jimin Guo;Shahrouz Amini;Qi Lei;Y. Ping;J. Agola;Lu Wang;Liang Zhou;Jiangfan Cao;Stefan Franco;Achraf Noureddine;Ali Miserez;Wei Zhu;C. Brinker
通讯作者：
C. Brinker

Bioinspired Cell Silicification: From Extracellular to Intracellular.

仿生细胞硅化：从细胞外到细胞内。

DOI：
10.1021/jacs.1c00814
发表时间：
2021-04-07
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Qi Lei;Jimin Guo;Fanhui Kong;Jiangfan Cao;Lu Wang;Wei Zhu;C. Brinker
通讯作者：
C. Brinker

Lipid-coated mesoporous silica nanoparticles for anti-viral applications via delivery of CRISPR-Cas9 ribonucleoproteins.

脂质涂层介孔二氧化硅纳米颗粒通过递送 CRISPR-Cas9 核糖核蛋白用于抗病毒应用。

DOI：
发表时间：
2023-04-27
期刊：
影响因子：
4.6
作者：
LaBauve, Annette E;Saada, Edwin A;Jones, Iris K A;Mosesso, Richard;Noureddine, Achraf;Techel, Jessica;Gomez, Andrew;Collette, Nicole;Sherman, Michael B;Serda, Rita E;Butler, Kimberly S;Brinker, C Jeffery;Schoeniger, Joseph S;Sasaki, Darryl;N
通讯作者：
N

Bridging the In Vitro to In Vivo gap: Using the Chick Embryo Model to Accelerate Nanoparticle Validation and Qualification for In Vivo studies.

弥合体外与体内差距：使用鸡胚模型加速体内研究的纳米颗粒验证和鉴定。