Targeting peripheral immune organs with self-assembling prodrug nanoparticles ameliorates allogeneic heart transplant rejection

by Selleckchem | Mar 18 2023

Organ transplantation has become a mainstay of therapy for patients with end-stage organ diseases. However, long-term administration of immunosuppressive agents, a scheme for improving the survival of transplant recipients, has been compromised by severe side effects and posttransplant complications. Therapeutic delivery targeting immune organs has the potential to address these unmet medical issues. Here, through screening of a small panel of mammalian target of rapamycin complex kinase inhibitor (TORKinib) compounds, a TORKinib PP242 is identified to be able to inhibit T cell function. Further chemical derivatization of PP242 using polyunsaturated fatty acids (i.e., docosahexaenoic acid) transforms this water-insoluble hydrophobic agent into a self-assembling nanoparticle (DHA-PP242 nanoparticle [DPNP]). Surface PEGylation of DPNP with amphiphilic copolymers renders the nanoparticles aqueously soluble for preclinical studies. Systemically administered DPNP shows tropism for macrophages within peripheral immune organs. Furthermore, DPNP regulates differentiation of adoptively transferred T cells in a macrophage-dependent manner in Rag1-/- mouse model. In an experimental model of heart transplantation, DPNP significantly extends the survival of grafts through inducing immune suppression, thus reducing the inflammatory response of the recipients. These findings suggest that targeted delivery of TORKinibs exploiting prodrug-assembled nanoparticle scaffolds may provide a therapeutic option against organ rejection.

Comments：

The statement describes a potential therapeutic approach for addressing the unmet medical needs of patients receiving organ transplants. The approach involves targeted delivery of a TORKinib inhibitor compound, PP242, to immune organs to suppress T cell function, which plays a critical role in graft rejection. The authors use chemical derivatization of PP242 to create a self-assembling nanoparticle (DPNP) that can target macrophages in peripheral immune organs. They also PEGylate the surface of DPNP to make it aqueously soluble for preclinical studies.

The authors demonstrate that systemic administration of DPNP leads to regulation of the differentiation of adoptively transferred T cells in a macrophage-dependent manner in a mouse model. They also show that DPNP can significantly extend the survival of grafts in an experimental model of heart transplantation by inducing immune suppression and reducing the inflammatory response of recipients.

Overall, the study suggests that targeted delivery of TORKinibs via prodrug-assembled nanoparticle scaffolds may provide a promising therapeutic option for preventing organ rejection in transplant recipients. However, further preclinical and clinical studies are needed to validate the safety and efficacy of this approach before it can be translated into clinical practice.