Nanotherapeutics for combined immunesuppression in organ transplantation

描述(申请人提供)：实体器官移植是治疗几种终末期疾病的有效方法。它的成功是由免疫抑制药物的开发推动的，这些药物会削弱对移植的免疫反应。为了避免移植排斥反应，必须定期联合服用这些药物。然而，这些药物会导致不良副作用，如高血压和糖尿病，并增加对机会性感染和癌症的易感性。在避免药物副作用的同时有效地输送组合免疫抑制剂的药物输送平台的开发将对固体器官移植领域产生革命性的影响。我们推测，将常用的免疫抑制药物雷帕霉素和霉酚酸共包裹到FDA批准的聚乳酸-乙醇酸(PLGA)纳米粒中将延长同种异体移植物的存活时间，并避免可溶性给药的毒副作用。此外，我们最近的一项研究表明，包裹霉酚酸的纳米粒靶向树突状细胞，并诱导负共刺激配体PD-L1在这些细胞上表达上调。由于可溶性给予雷帕霉素可抑制树突状细胞上激活的共刺激配体的上调，我们还假设共包裹雷帕霉素和霉酚酸将在树突状细胞中诱导一种前免疫耐受表型，并促进移植耐受的发展。为了研究雷帕霉素和霉酚酸纳米粒的联合包裹是否延长了同种异体移植物的存活时间，避免了毒副作用，并增强了移植耐受的发展，我们将在体外完成概念验证研究后使用实验性小鼠移植模型，这两种药物都已针对NP药物输送进行了优化。我们预计，我们的研究预期结果将为一项开创性的临床研究奠定基础，即通过纳米颗粒将联合免疫抑制药输送到器官移植受者，这将对固体器官移植领域产生革命性影响。

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.