Targeted Drug Delivery Via Nanoparticles Could Help Repair Transplant Organs

Scientists have designed targeted nanoparticles to aid the therapeutic delivery of drugs directly to organs. This new technique, ex vivo normothermic machine perfusion (NMP) could increase the number of viable organs available for transplantation. More specifically, it enables delivery of drugs to vascular endothelial cells (ECs) – the first point of contact with a transplant recipient’s immune system. These cells are particularly vulnerable to ischemia-reperfusion injury and damage from antidonor antibodies.

There are two key challenges associated with kidney transplantation. Firstly, shortage of suitable organs, and secondly, the rate of late graft failure.¹ There are ~116,000 people in the USA currently awaiting an organ transplant, of these a staggering 96,000 are specifically waiting for a kidney.² However, only ~18,000 transplantations are performed each year,³ which is largely due to a short supply of viable organs.

This novel strategy could help repair organs that would otherwise be dismissed as suitable for transplantation, and could increase the pool of suitable organs available to transplant patients. This research was published in the November 29 issue of Science Translational Medicine.

We spoke to Prof. Jordan S. Pober, senior author of the paper: “This is a promising approach to evaluate and improve the condition of solid organs prior to transplantation. We and others have exploited this methodology to propose treating the organ ex vivo to further improve its condition. The two novel aspects of our study are the proposal to use slowly hydrolysable polymeric nanoparticles as a delivery vehicle so that benefit of treatment can be long lasting and to target the vascular endothelium of the organ as these cells form the interface between the graft and the host’s immune system.”

“The initial encounter of the host’s immune system with the graft has been shown to have a major impact on how vigorous the host’s immune response will be and this affects both short-term and long-term transplant outcomes. For example, improving graft health to reduce inflammation or preventing host pre-formed antibodies from injuring the graft in the peri-transplant period have both led to improved long-term graft survival.” explained Pober.

The researchers had previously investigated the use of nanoparticles for the long-term delivery of drugs, however ensuring that an adequate number of these particles are delivered to the target organ remained a challenge. In their new publication, Teitjen et al. explain that by studying EC surface markers in human kidneys, they were able to identify a specific protein, CD31, that could potentially be exploited. By coating the nanoparticles with an anti-CD31 antibody, it was possible to increase the targeting of the particles to the graft ECs. When comparing coated and uncoated nanoparticles they were able to determine that CD31-targeting enhanced the accumulation of the drug filled nanoparticles by ~five-fold. There was some nonspecific nanoparticle accumulation, but this was primarily observed in areas of reduced circulation within the kidney.

This study suggests that renal vascular ECs are a potential target for therapies aimed at improving transplant outcomes.

Commenting on future research direction, Pober added: “So far we have shown that one can use antibody conjugated to a polymeric nanoparticle to increase selective targeting of the vascular endothelium of a human kidney.”

“The next two tasks will be to further improve targeting, perhaps with other antibodies or combinations of antibodies and to obtain a therapeutic response with a small molecule drug or an siRNA. Both efforts are in progress as an ongoing collaboration between Yale and University of Cambridge investigators.”