Nanoparticles based on histone deacetylase inhibitors for combination treatments

 描述(由申请人提供)：癌症的发生和发展由遗传和表观遗传变化决定。组蛋白脱乙酰酶(HDAC)是一种积极参与染色质重塑的酶，在多种类型的人类肿瘤中异常表达和失调。HDAC抑制剂(HDACi)代表了一类新兴的药物，具有广泛的抗癌作用。由于其广泛的抗癌活性，HDACi特别适合与传统抗癌药物的协同组合。选择性地提供HDACi与传统抗癌药物的组合的能力有可能极大地提高许多类型癌症的治疗方案和疗效。这项提议的目的是开发能够靶向、同时、联合地将HDACi和抗癌药物输送到肺癌中的纳米颗粒。中心假说是，使用具有高含量HDACi侧链的新型可生物降解聚己内酯(HDPCL)将增强由HDPCL制备的针对高表达粘蛋白1的肺癌的纳米粒传递的多种抗癌药物的活性。该假说基于我们目前对HDPCL的研究以及HDAC抑制在增强多种抗癌药物活性方面的公认作用。这一应用的总体目标将通过追求三个具体目标来实现：1)合成具有侧链HDACi基团的可生物降解的聚己内酯(HDPCL)；2)评估HDPCL传递是否提高了肺癌细胞中的药物活性；以及3)体内确定HDPCL传递是否提高了原位肺癌模型的抗肿瘤活性。这种方法是创新的，因为新型的可生物降解聚酯具有高HDACi负载量(高达59wt%)和受控释放HDACi，适合于传统抗癌药物的联合给药。这项拟议的研究具有重要意义，因为它将建立一种广泛适用和通用的方法，用于同时靶向输送化疗药物和HDACi，以改善肺癌的输送和治疗结果。依赖于具有协同或相加效应的活性药物组合的方法有可能极大地提高癌症治疗的疗效。

 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.