Backbone Degradable Polymer-drug Conjugates for the Treatment of Ovarian Cancer
用于治疗卵巢癌的主链可降解聚合物-药物缀合物
基本信息
- 批准号:8921139
- 负责人:
- 金额:$ 49.24万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-09-26 至 2017-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdverse effectsAnimal ModelAntimitotic AgentsAntineoplastic AgentsAwardBiocompatibleBiodistributionCancer ModelCell divisionClinicClinical TrialsCollaborationsCombined Modality TherapyCytidineDNADataDevelopmentDoseDose-LimitingDrug CarriersDrug CombinationsDrug Delivery SystemsEvaluationFDA approvedGenerationsGoalsHealthInvestigational DrugsLaboratoriesLegal patentMalignant neoplasm of ovaryMaximum Tolerated DoseMicrotubulesMolecular WeightMusOligopeptidesOrganOvarian CarcinomaPaclitaxelPermeabilityPharmaceutical PreparationsPhasePolymersPublicationsRegimenResearchResource AllocationSideSiteSmall Business Technology Transfer ResearchStagingSystemTherapeuticTimeTimeLineToxic effectTranslationsTreatment EfficacyTreatment ProtocolsTreatment outcomeUnited States National Institutes of HealthVertebral columnX-Ray Computed Tomographybasebiodegradable polymercancer therapychemical synthesischemotherapycopolymerdesigngemcitabinein vivoinnovationmethacrylamidenovelnucleoside analogovarian neoplasmpreclinical studyprotein aminoacid sequencescale upsingle photon emission computed tomographysuccesstripolyphosphatetumor
项目摘要
DESCRIPTION (provided by applicant): The purpose of this Phase II STTR project is to develop a polymeric system for the combination delivery of two antineoplastic agents, gemcitabine and paclitaxel. Based on the successful results of the STTR Phase I award, this Phase II proposal details the rationale and research plan for the synthesis and evaluation of in vivo efficacy of two novel macromolecular therapeutics with diverse and complementary mode of action for the treatment of ovarian carcinoma. Their design is based on new, innovative long-circulating backbone degradable N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer - drug conjugates. The polymeric carrier will be composed of alternating HPMA copolymer segments (blocks) and enzymatically degradable oligopeptide sequences. Each construct will contain multiple copies of either gemcitabine or paclitaxel. The drugs are attached to the backbone via a lysosomally degradable spacer that will allow intracellular release and bioactivity. The choice of drugs bodes well for the success of the project. Gemcitabine is a synthetic nucleoside analog of cytidine. Its triphosphate metabolite is incorporated into DNA, thereby stopping cell division. Gemcitabine has demonstrated activity in several ovarian cancer models and has been approved by FDA for combination therapy of ovarian cancer. Paclitaxel is a mitotic inhibitor, which acts by stabilizing microtubules, thereby inhibiting their breakdown during cellular division It is currently indicated as first-line and subsequent therapy for the treatment of advanced stages of ovarian cancer. The long circulating time of the new, innovative backbone degradable carriers will result in augmented tumor accumulation due to the EPR (enhanced permeability and retention) effect. In addition, the combination of two polymer-drug conjugates with diverse mechanisms of action will result in enhanced efficacy of ovarian cancer treatment and minimal adverse effects. The specific aims of the proposal are three-fold: a) To scale up of the synthesis and to characterize backbone degradable HPMA copolymer-drug (gemcitabine and paclitaxel) conjugates containing enzymatically degradable sequences in the backbone and in side chains; b) To establish the maximum tolerated dose (MTD) as well as the acute toxicity of the conjugates and their combination in vivo; and c) To evaluate the biodistribution, clearance, anticancer efficacy and dose escalation studies of the conjugates in vivo. The ultimate goal of this project is to develop an effective and marketable drug combination with a novel drug delivery system for the treatment of ovarian cancer where the drugs are localized at the site of the tumor, adverse effects of chemotherapy are minimized and efficacy maximized.
描述(由申请人提供):该II期STTR项目的目的是开发一种聚合物系统,用于吉西他滨和紫杉醇两种抗癌药物的联合给药。基于STTR I期奖的成功结果,该II期提案详细介绍了两种新型大分子治疗剂的合成和体内疗效评价的原理和研究计划,这两种治疗卵巢癌的新型大分子治疗剂具有多样和互补的作用模式。他们的设计是基于新的,创新的长循环主链可降解的N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-药物缀合物。聚合物载体将由交替的HPMA共聚物链段(嵌段)和酶可降解的寡肽序列组成。每个构建体将含有吉西他滨或紫杉醇的多个拷贝。药物通过溶酶体可降解的间隔物连接到骨架上,这将允许细胞内释放和生物活性。药物的选择预示着该项目的成功。吉西他滨是胞苷的合成核苷类似物。它的三磷酸代谢物被掺入DNA,从而停止细胞分裂。吉西他滨已在几种卵巢癌模型中显示出活性,并已被FDA批准用于卵巢癌的联合治疗。紫杉醇是一种有丝分裂抑制剂,其作用是稳定微管,从而抑制它们在细胞分裂过程中的分解。目前,紫杉醇被用作治疗晚期卵巢癌的一线和后续治疗。由于EPR(增强的渗透性和保留)效应,新的、创新的主链可降解载体的长循环时间将导致肿瘤累积增加。此外,具有不同作用机制的两种聚合物-药物缀合物的组合将导致卵巢癌治疗的增强功效和最小的副作用。该提案的具体目标有三个方面:a)扩大合成规模并表征主链可降解HPMA共聚物-药物B)确定缀合物及其组合的最大耐受剂量(MTD)以及体内急性毒性;和c)评估缀合物的体内生物分布、清除、抗癌功效和剂量递增研究。该项目的最终目标是开发一种有效且可销售的药物组合,其具有用于治疗卵巢癌的新型药物递送系统,其中药物定位于肿瘤部位,将化疗的副作用降至最低,并将疗效最大化。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JINDRICH H. KOPECEK其他文献
JINDRICH H. KOPECEK的其他文献
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{{ truncateString('JINDRICH H. KOPECEK', 18)}}的其他基金
Coiled-coil Based Drug-Free Macromolecular Therapeutics
基于卷曲线圈的无药大分子治疗
- 批准号:
8291234 - 财政年份:2011
- 资助金额:
$ 49.24万 - 项目类别:
Coiled-coil Based Drug-Free Macromolecular Therapeutics
基于卷曲线圈的无药大分子治疗
- 批准号:
8645644 - 财政年份:2011
- 资助金额:
$ 49.24万 - 项目类别:
Coiled-coil Based Drug-Free Macromolecular Therapeutics
基于卷曲线圈的无药大分子治疗
- 批准号:
8457100 - 财政年份:2011
- 资助金额:
$ 49.24万 - 项目类别:
Coiled-coil Based Drug-Free Macromolecular Therapeutics
基于卷曲线圈的无药大分子治疗
- 批准号:
8021749 - 财政年份:2011
- 资助金额:
$ 49.24万 - 项目类别:
Backbone Degradable Polymer-drug Conjugates for the Treatment of Ovarian Cancer
用于治疗卵巢癌的主链可降解聚合物-药物缀合物
- 批准号:
8779604 - 财政年份:2011
- 资助金额:
$ 49.24万 - 项目类别:
DOUBLE-TARGETED MACROMOLECULAR THERAPEUTICS FOR THE TREATMENT OF PROSTATE CANCER
治疗前列腺癌的双靶点大分子疗法
- 批准号:
7759540 - 财政年份:2008
- 资助金额:
$ 49.24万 - 项目类别:
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