Apoptosis Inducing to Enhance Tumor Targeting

描述（申请人提供）：晚期胰腺癌患者预后惨淡，中位生存期不足6个月。这些患者通常表现为腹膜腔内多发实体瘤；采用各种化疗药物进行全身静脉（iv）治疗，总有效率<10%，生存优势很小。腹腔内（ip）疗法已被用于向位于腹腔的肿瘤输送高浓度药物。ip治疗的效用和疗效受到两个问题的限制。首先，药物对肿瘤的渗透通常局限于肿瘤周围。其次，ip治疗与长期留置导管引起的感染和由于局部药物浓度高引起的局部毒性（即腹痛）有关。在第一阶段SBIR资助期间，我们开发了一种双组分、生物相容性、可生物降解、控释的聚合紫杉醇负载微颗粒。第一种成分释放少量剂量诱导细胞凋亡，降低肿瘤细胞密度，破坏肿瘤结构，扩大间质空间，从而促进药物/颗粒渗入肿瘤。第二组分提供持续的药物递送，从而消除了留置导管的使用并减少了潜在的局部毒性。两种药物释放率也使快速和缓慢生长的肿瘤得到控制。此外，选择颗粒大小和表面性质来增强颗粒在腹腔内的滞留和颗粒在肿瘤结节表面的定位。这种专利产品被称为肿瘤启动微粒（TPM）。我们已完成的研究表明TPM定位于肿瘤表面，穿透并驻留在肿瘤基质中。在患有快速生长的人类胰腺Hs766T异种移植肿瘤和缓慢生长的人类卵巢SKOV3异种移植肿瘤的小鼠的早期和晚期疾病（由癌变或腹水形成表明）中，TPM也产生了显著的生存益处（与未治疗的对照组相比，生存期延长3倍）。目前二期SBIR申请的总体目标是继续开发TPM，包括从FDA获得IND。这三个目标是：(a)建立规模化GMP产品的规格；(b)向FDA提交IND；(c)制订临床发展策略。

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.