Apoptosis Inducing to Enhance Tumor Targeting

描述（由申请人提供）：晚期胰腺癌患者预后不良，中位生存时间不到6个月。这些患者通常在腹膜腔中存在多个实体瘤;使用各种化疗剂的全身静脉内（iv）治疗产生<10%的总体反应率，几乎没有生存优势。腹膜内（ip）治疗已被用于向位于腹膜腔中的肿瘤递送高浓度的药物。ip疗法的效用和功效受到两个问题的限制。首先，药物渗透到肿瘤中通常限于外周。其次，ip治疗与由于长期使用留置导管引起的感染和局部毒性（即，腹痛），这是由于高的局部药物浓度。在第一阶段SBIR赠款，我们开发了一种双组分，生物相容性，可生物降解，控释聚合物紫杉醇负载微粒。第一组分释放一小部分剂量以诱导细胞凋亡，降低肿瘤细胞密度，破坏肿瘤结构并扩大间质空间，从而促进药物/颗粒渗透到肿瘤中。第二组分提供持续的药物递送，从而消除了留置ip导管的使用，并降低了潜在的局部毒性。这两种药物释放速率也使得能够控制快速和缓慢生长的肿瘤。此外，选择颗粒尺寸和表面性质以增强颗粒在腹膜腔中的保留和颗粒在肿瘤结节表面上的定位。这种专利产品被称为肿瘤引发微粒（TPM）。我们已完成的研究表明TPM定位于肿瘤表面，渗透并驻留在肿瘤基质中。TPM还在携带快速生长的人胰腺Hs 766 T异种移植肿瘤和缓慢生长的人卵巢SKOV 3异种移植肿瘤的小鼠的早期和晚期疾病（由癌病或腹水形成指示）中产生显著的存活益处（与未处理的对照相比，存活时间长3倍）。目前II期SBIR申请的总体目标是继续TPM的开发，包括从FDA获得IND。这三个目标是：（a）建立扩大GMP产品的质量标准;（B）向FDA提交IND;（c）制定临床开发策略。

DESCRIPTION (provided by applicant): Patients with advanced pancreatic cancer have a bleak prognosis, with a median survival time of less than 6 months. These patients usually present with multiple solid tumors in the peritoneal cavity; systemic intravenous (iv) therapy with various chemotherapeutic agents produce an overall response rate of <10% with little survival advantage. Intraperitoneal (ip) therapy has been used to deliver high drug concentrations to tumors located in the peritoneal cavity. The utility and efficacy of ip therapy are limited by two problems. First, drug penetration into a tumor is usually restricted to the periphery. Second, ip therapy is associated with infection due to prolonged use of indwelling catheter and with local toxicity (i.e., abdominal pain) due to the high local drug concentrations. During the Phase I SBIR grant, we developed a two-component, biocompatible, biodegradable, controlled-release polymeric paclitaxel-loaded microparticles. The first component releases a small fraction of the dose to induce apoptosis, reduce the tumor cell density, disrupt the tumor structure and expand the interstitial space, and thereby facilitates the penetration of drug/particles into tumors. The second component provides sustained drug delivery and thereby eliminates the use of indwelling ip catheter and reducing the potential local toxicity. The two drug release rates also enabled the control of both rapidly and slowly growing tumors. In addition, the particle size and surface properties were selected to enhance the particle retention in the peritoneal cavity and the particle localization on the surface of tumor nodules. This proprietary product is referred to as tumor-priming microparticles (TPM). Our completed studies showed TPM localized on tumor surface, penetrated and resided in tumor matrix. TPM also produced significant survival benefits (3 times longer survival compared to untreated controls) in both early and late stage diseases (indicated by carcinomatosis or ascites formation) in mice bearing the rapidly growing human pancreatic Hs766T xenograft tumors and the slowly growing human ovarian SKOV3 xenograft tumors. The overall goal of the present Phase II SBIR application is to continue the development of TPM, including obtaining an IND from FDA. The three aims are to (a) establish specifications for scale-up GMP products; (b) file IND with FDA; (c) develop a clinical development strategy.