A New Albumin Based Nanomedicine To Improving Tacrolimus Safety And Lymphatic Targeting Efficiency

Objectives:The increasing demand of organ transplantation and the frequent occurrence of transplant rejection necessitate the development of new therapies.Immunosuppressant marks an effective therapeutic strategy but is usually impeded by its toxicity,untargeted distribution,and high pharmacokinetic variability,for an instance,tacrolimus(TAC),due to its low solubility in water,the commercial product named Prograf injection which contains polyoxyethylene hydrogenated castor oil and ethanol to dissolve and aggravates its side effects,limits clinical use.The emergence of nanoformulations largely addresses these problems owing to their flexible engineering capability,however,the excessive use of chemical solvents,the hazardous pharmaceutical residues,and the complex fabrication process attract the major concerns.because of its high toxicity and pharmacokinetic variability,reduce its therapeutic index,are often limited in clinical applications,However,human serum albumin is non-toxic,non-immunogenicity material,which makes it an excellent nanocarrier.Method:In this work,we reported a novel human serum albumin(HSA)nanoformulation loaded with a well-known immunosuppressant tacrolimus(TAC)(termed TAC-HSA-NPs).Our nanoformulation is fabricated via a self-assembly procedure of albumin in aqueous solution without any toxic substance involved,minimizing the adverse effect as well as environmental hazard.We performed a series of tests on this nanodrug,including its physical properties,pharmacokinetics,inhibition of lymphocyte proliferation and activation in vitro,and evaluation of its efficacy in vivo using a mouse allogeneic heart transplantation model.Results:By adjusting the molar ratio of HSA to TAC,we were able to take control of several key parameters of the derived nanoparticles,such as loading capacity and particle size distribution.Under the molar ratio of HSA:TAC=1:10,TAC-HSA-NPs showed a mean size of 164±51 nm with desirable water solubility,reliable pharmacokinetic stability,prolonged blood circulation as well as decreased renal toxicity.More importantly,both in vivo mice allo-heart transplantation and ex vivo model verified the efficient lymphatic targeting of TAC-HSA-NPs,which is of crucial significance for Immunosuppression related with transplant rejection.Conclusions:Overall,our study proposed a new line of thinking on the fabrication of nanoformulations and confirmed the potential use of TAC-HSA-NPs in of organ transplantation.