Dendritic Biomaterials for Oral Delivery of Chemotherapeutics

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外途径给药。由于口服吸收仍然是首选的给药途径，许多药理活性药物以及聚合物在口服给药时具有较差的全身可利用性。我们的初步数据表明，聚胺胺（PAMAM）树状大分子可以有效地跨上皮细胞单层转移，并可以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进入体循环的口服吸收，并通过创建共轭递送系统将其引导到目标部位。在目前的提案中，我们旨在评估PAMAM树状大分子的结构特征对其经上皮转运的影响，并利用其渗透增强作用来提高口服生物利用度，并利用其大分子性质来促进模型药物的靶向。本提案的长期目标是开发基于PAMAM树状大分子的靶向口服药物递送聚合物系统。我们提出的研究的中心假设是，可吸收性差的药物的渗透和靶向潜力通过与PAMAM树状大分子结合而增强。为了验证我们的假设，我们将研究以下具体目的：1)评估电荷和药物负荷对PAMAM树状大分子肠道运输和细胞毒性的影响。2)评价树状聚合物-药物偶联物的体外稳定性和原位生物利用度。3)在结直肠癌肝转移小鼠模型中评价其体内生物利用度、抗肿瘤功效和毒性。4)阐明PAMAM树状大分子的肠转运机制。通过评估结构特征对通透性和稳定性的影响，我们期望找到原型PAMAM树状大分子，可以增加SN38的口服利用度，表现出最小的毒性，并有效地靶向肝转移。对转运机制的描述将有助于设计用于口服给药的新型聚合物载体。从长远来看，这可能允许使用定制的PAMAM树状大分子作为聚合物载体，以更可控和更有针对性的方式通过Gl道输送各种治疗分子。

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.