Dendritic Biomaterials for Oral Delivery of Chemotherapeutics

用于口服化疗药物的树突状生物材料

• 批准号: 7627049
• 负责人: Hamid Ghandehari
• 金额: $ 31.34万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7627049
• 关键词: Biocompatible Materials; Biological Availability; Biopolymers; Blood Circulation; Camptothecin Analogue; Characteristics; Charge; Chemistry; Colorectal Cancer; Data; Dendrimers; Drug Delivery Systems; Drug Transport; Drug toxicity; Drug usage; Environment; Enzymes; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Exhibits; Hydrolysis; In Situ; In Vitro; Intestines; Label; Metastatic Neoplasm to the Liver; Modeling; Mucous Membrane; Mus; Nature; Oral; Pathway interactions; Permeability; Pharmaceutical Preparations; Polymers; Process; Research; Route; SN-38; Site; System; Testing; Therapeutic; Toxic effect; Water; absorption; base; cytotoxicity; design; gastrointestinal; improved; in vivo; intestinal epithelium; monolayer; novel; prototype; size; small molecule; targeted delivery

DESCRIPTION (provided by applicant): Targeted delivery of drugs using water-soluble polymeric carriers improves efficacy and reduces toxicity. However, the large size of most biopolymers necessitates administration via the parenteral route. As oral absorption remains the preferred route of administration, many pharmacologically active drugs as well as polymers have poor systemic availability when administered orally. Our preliminary data indicate that poly(amidoamine) (PAMAM) dendrimers efficiently translocate across epithelial cell monolayers and can effectively increase the transfer of small molecules. Thus, this polymeric carrier may be used to improve the oral absorption of therapeutic molecules into the systemic circulation and direct them to the target sites via the creation of a conjugate delivery system. In the current proposal we aim to evaluate the influence of structural features of PAMAM dendrimers on their transepithelial transport and capitalize on both their permeation enhancing effects to increase the oral bioavailability and their macromolecular nature to facilitate targeting of a model drug. The long-term objective of this proposal is to develop polymeric systems based on PAMAM dendrimers for targeted oral drug delivery. The central hypothesis to our proposed research is that the permeation and targeting potential of poorly absorbable drugs is enhanced by conjugation to PAMAM dendrimers. To test our hypothesis, we will study the following Specific Aims: 1) To evaluate the influence of charge and drug loading on intestinal transport and cytotoxicity of PAMAM dendrimers. 2) To evaluate the in vitro stability and in situ bioavailability of dendrimer-drug conjugates. 3) To evaluate the in vivo bioavailability, antitumor efficacy and toxicity of the conjugates in a murine model of liver metastasis of colorectal cancer. 4) To delineate the intestinal transport mechanism(s) of PAMAM dendrimers. By evaluating the influence of structural features on permeability and stability we expect to find prototype PAMAM dendrimers that can increase oral availability of SN38, exhibit minimal toxicity, and target the drug effectively to liver metastases. Delineation of the mechanism(s) of transport will aid in the rationale design of novel polymeric carriers for oral delivery. In the long term this may allow for the delivery of a variety of therapeutic molecules in a more controlled and targeted manner across the Gl tract using tailor-made PAMAM dendrimers as polymeric carriers.

描述（由申请人提供）：使用水溶性聚合物载体靶向递送药物可提高疗效并降低毒性。然而，大多数生物聚合物的大尺寸需要通过肠胃外途径施用。由于口服吸收仍然是优选的给药途径，因此当口服给药时，许多具有生物活性的药物以及聚合物具有较差的全身利用度。我们的初步数据表明，聚酰胺-胺（PAMAM）树枝状聚合物有效地跨上皮细胞单层转运，并能有效地增加小分子的转移。因此，该聚合物载体可用于改善治疗分子口服吸收进入体循环，并通过产生缀合物递送系统将它们引导至靶位点。在目前的提案中，我们的目标是评估PAMAM树枝状聚合物的结构特征对它们的跨上皮转运的影响，并利用它们的渗透增强作用来增加口服生物利用度和它们的大分子性质来促进模型药物的靶向。该提案的长期目标是开发基于PAMAM树枝状聚合物的聚合物系统用于靶向口服药物递送。我们所提出的研究的中心假设是，通过与PAMAM树枝状聚合物缀合，可增强吸收性差的药物的渗透和靶向潜力。为了验证我们的假设，我们将研究以下具体目的：1）评价电荷和药物负载对PAMAM树枝状聚合物的肠道转运和细胞毒性的影响。2)评价树状大分子-药物偶联物的体外稳定性和原位生物利用度。3)在结直肠癌肝转移的小鼠模型中评价缀合物的体内生物利用度、抗肿瘤功效和毒性。4)描述PAMAM树枝状聚合物的肠道转运机制。通过评估结构特征对渗透性和稳定性的影响，我们期望找到原型PAMAM树枝状聚合物，其可以增加SN 38的口服利用度，表现出最小的毒性，并将药物有效地靶向肝转移。运输机制的描述将有助于合理设计用于口服递送的新型聚合物载体。从长远来看，这可以允许使用定制的PAMAM树枝状聚合物作为聚合物载体以更受控和靶向的方式递送各种治疗分子穿过胃肠道。