Nanoparticles based on histone deacetylase inhibitors for combination treatments

基于组蛋白脱乙酰酶抑制剂的纳米颗粒用于联合治疗

• 批准号: 9043064
• 负责人: David Oupicky
• 金额: $ 22.73万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043064
• 关键词: Animals; Antineoplastic Agents; Apoptosis; Cancer Model; Cancer cell line; Cell Cycle Arrest; Clinical; Complex; Disease; Drug Combinations; Encapsulated; Enzymes; Epigenetic Process; Exhibits; Glycoproteins; Health; Hematologic Neoplasms; Histone Deacetylase Inhibitor; Histones; Human; In Vitro; Libraries; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Molecular Weight; Mucin 1 protein; Mutation; Paclitaxel; Pharmaceutical Preparations; Phenylbutyrates; Polyesters; Property; Public Health; Research; Role; System; Testing; TimeLine; Treatment outcome; anticancer activity; base; cancer cell; cancer initiation; cancer therapy; cancer type; caprolactone; chromatin remodeling; copolymer; effective therapy; improved; in vivo; inhibitor/antagonist; innovation; monomer; nanoparticle; new technology; novel; overexpression; particle; polycaprolactone; preclinical study; senescence; small molecule; success; targeted delivery; therapy outcome; tumor progression; valproate

 DESCRIPTION (provided by applicant): Cancer initiation and progression is determined by both genetic and epigenetic changes. Histone deacetylases (HDAC) are enzymes actively involved in chromatin remodeling and are aberrantly expressed and dysregulated in multiple types of human cancers. HDAC inhibitors (HDACi) represent an emerging class of drugs that exhibit a broad range of anticancer effects. As a result of their broad anticancer activity, HDACi are particularly well suited for synergistic combinations with conventional anticancer drugs. The ability to selectively deliver combinations of HDACi with conventional anticancer drugs has the potential to greatly enhance the treatment repertoire and efficacy for many types of cancers. The objective of this proposal is to develop nanoparticles capable of targeted, simultaneous, combined delivery of HDACi and anticancer drugs into lung cancer. The central hypothesis is that using novel biodegradable polycaprolactones with high content of pendant HDACi moieties (HDPCL) will enhance activity of multiple anticancer drugs delivered by nanoparticles prepared from HDPCL and targeted to lung tumors overexpressing mucin 1. The hypothesis is based on our current studies with HDPCL and the well-established role of HDAC inhibition in enhancing activity of multiple anticancer drugs. The overall objective of this application will be achieved b pursuing three specific aims: 1) synthesize biodegradable polycaprolactones with pendant HDACi groups (HDPCL); 2) evaluate if delivery by HDPCL improves drug activity in lung cancer cells; and 3) determine in vivo if HDPCL delivery improves antitumor activity in orthotopic lung cancer model. The approach is innovative because of the novel type of biodegradable polyesters with high HDACi loading (up to 59 wt %) and controlled HDACi release suitable for combination delivery of conventional anticancer drugs. The proposed research is significant because it will establish a widely applicable and versatile method for simultaneous, targeted delivery of chemotherapeutics and HDACi to improve delivery and therapeutic outcome in lung cancer. Approaches that rely on combinations of active agents with synergistic or additive effect have the potential to greatly enhance the efficacy of cancer therapy.

 描述（由申请人提供）：癌症的发生和进展由遗传和表观遗传变化决定。组蛋白脱乙酰酶（HDAC）是活跃参与染色质重塑的酶，并且在多种类型的人类癌症中异常表达和失调。HDAC抑制剂（HDACi）代表了一类新兴的药物，表现出广泛的抗癌作用。由于其广泛的抗癌活性，HDACi特别适合与常规抗癌药物协同组合。选择性递送HDACi与常规抗癌药物的组合的能力具有极大地增强许多类型癌症的治疗谱和功效的潜力。该提案的目的是开发能够将HDACi和抗癌药物靶向、同时、联合递送到肺癌中的纳米颗粒。中心假设是使用具有高含量的悬垂HDACi部分（HDPCL）的新型可生物降解的聚己内酯将增强由HDPCL制备的纳米颗粒递送的多种抗癌药物的活性，并且靶向过表达粘蛋白1的肺肿瘤。该假设是基于我们目前对HDPCL的研究以及HDAC抑制在增强多种抗癌药物活性中的公认作用。本申请的总体目的将通过追求三个具体目标来实现B：1）合成具有HDACi侧基的可生物降解的聚己内酯（HDPCL）; 2）评估通过HDPCL的递送是否改善肺癌细胞中的药物活性;和3）在体内确定HDPCL递送是否改善原位肺癌模型中的抗肿瘤活性。该方法是创新的，因为具有高HDACi负载（高达59重量%）和受控HDACi释放的新型生物可降解聚酯适合于常规抗癌药物的组合递送。这项研究意义重大，因为它将建立一种广泛适用的通用方法，用于同时靶向递送化疗药物和HDACi，以改善肺癌的递送和治疗效果。依赖于具有协同或累加效应的活性剂的组合的方法具有极大地增强癌症治疗的功效的潜力。

项目成果

Synthesis and Characterization of New Chlorhexidine-Containing Nanoparticles for Root Canal Disinfection.

• DOI: 10.3390/ma9060452
• 发表时间: 2016-06-07
• 期刊: Materials (Basel, Switzerland)
• 作者: Haseeb R;Lau M;Sheah M;Montagner F;Quiram G;Palmer K;Stefan MC;Rodrigues DC
• 通讯作者: Rodrigues DC

HDAC Inhibitor Conjugated Polymeric Prodrug Micelles for Doxorubicin Delivery.

• DOI: 10.1039/c6tb03038f
• 发表时间: 2017-03-21
• 期刊: Journal of materials chemistry. B
• 作者: Senevirathne SA;Washington KE;Miller JB;Biewer MC;Oupicky D;Siegwart DJ;Stefan MC
• 通讯作者: Stefan MC

Histone Deacetylase Inhibitor (HDACi) Conjugated Polycaprolactone for Combination Cancer Therapy.

• DOI: 10.1021/acs.biomac.8b00221
• 发表时间: 2018-03-12
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Kularatne RN;Washington KE;Bulumulla C;Calubaquib EL;Biewer MC;Oupicky D;Stefan MC
• 通讯作者: Stefan MC