Nanotherapeutics for combined immunesuppression in organ transplantation

描述（申请人提供）：实体器官移植是几种终末期疾病的有效治疗方法。它的成功是由免疫抑制药物的发展所推动的，这种药物会损害对移植的免疫反应。为了避免移植排斥反应，这些药物的组合必须定期服用。然而，这些药物会引起不良的副作用，如高血压和糖尿病，以及增加对机会性感染和癌症的易感性。开发既能有效地递送联合免疫抑制剂，又能避免药物引起的副作用的药物递送平台，将对实体器官移植领域产生革命性的影响。我们假设，将常用的免疫抑制药物雷帕霉素和霉酚酸共包封到FDA批准的聚乳酸-羟基乙酸（PLGA）纳米颗粒中，将延长同种异体移植物的存活时间，并避免可溶性给药药物的毒副作用。此外，我们最近的一项研究表明，用霉酚酸包裹的纳米颗粒靶向树突状细胞，并诱导这些细胞上PD-L1（一种负共刺激配体）的上调。由于已知可溶性雷帕霉素会损害树突状细胞上共刺激配体激活的上调，我们也假设雷帕霉素和霉酚酸的共包封将诱导树突状细胞的前免疫耐受表型，并增强移植耐受的发展。为了研究纳米颗粒内联合包埋雷帕霉素和霉酚酸是否能延长同种异体移植物的存活时间，避免药物毒副作用，并促进移植耐受性的发展，我们将在体外完成概念验证研究后采用实验性小鼠移植模型，并对两种药物进行了NP药物递送优化。我们期望我们研究的预期结果将为突破性的临床研究奠定基础，通过纳米颗粒向器官移植受体提供联合免疫抑制剂，这将对实体器官移植领域产生变革。

DESCRIPTION (provided by applicant): Solid organ transplantation is an effective therapy for several end-stage diseases. Its success has been driven by the development of immune suppressive medications that impair the immune response to the transplant. To avoid transplant rejection, combinations of these medications must be taken regularly. However, these medications induce undesirable side effects, such as hypertension and diabetes, as well as increased susceptibility to opportunistic infections and cancer. The development of drug delivery platforms that effectively deliver combination immune suppressants while avoiding drug-induced side effects would be transformative for the solid organ transplant field. We hypothesize that co-encapsulation of the commonly employed immune suppressive medications rapamycin and mycophenolic acid into FDA- approved poly(lactic-co-glycolic acid) (PLGA) nanoparticles will prolong allograft survival and avoid the toxic side effects of the soluble administered drugs. In addition, one of our recent studies demonstrated that nanoparticles encapsulated with mycophenolic acid target dendritic cells and induce the upregulation of PD-L1, a negative costimulatory ligand, on these cells. As soluble administered rapamycin is known to impair the upregulation of activating costimulatory ligands on dendritic cells, we also hypothesize that co- encapsulation of rapamycin and mycophenolic acid will induce a pro immune tolerant phenotype in dendritic cells and enhance the development of transplant tolerance. To investigate whether combined encapsulation of rapamycin and mycophenolic acid within nanoparticles prolongs allograft survival, avoids toxic drug side effects and enhances the development of transplant tolerance, we will employ experimental murine transplant models after proof-of-concept studies have been completed in vitro, and both agents have been optimized for NP drug delivery. We expect that the anticipated results of our study will lay the foundation to a ground-breaking clinical study to deliver combination immune suppressants to organ transplant recipients via nanoparticles, which would be transformative to the solid organ transplant field.