Study On NO-Donor Linked PepT1 Targeting Multifunctional Nanodrug Delivery System

Advances in nano-drug delivery systems have made it possible to target delivery of traditional drugs,thereby improving the pharmacokinetic properties,enhancing the accumulation of solid tumors and reducing toxic and side effects.In this paper,functional molecules with hydrophobic properties were modified on hydroxyl groups of polyethylene glycol(PEG)by hydrophilic interaction: The L-Val-L-Val fragment targeting PepT1 was modified by hydroxyl group at one end,which increased the accumulation of nano-polymer in the tumor site and inhibited the growth of tumor cells;On the other hand,We synthesized a novel nitric oxide(NO)donor and introduced it to the other end of PEG.By releasing NO from the tumor site,it can play a synergistic role in the inhibition of cancer cells.In addition,we further modified a hypoxia inhibitor YC-1 on the NO donor to obtain NO donor-YC-1 inhibitor conjugate(NO-YC-1),which can achieve the goal of hypoxia therapy by inhibiting hypoxia inducible factor-1?(HIF-1?).Finally,we modified NO-YC-1 to another hydroxyl end of polyethylene glycol to form a multifunctional Nanopolymer(L-Val-L-Val-PEG-NO-YC-1)with NO donor bridging chain.The nano-polymer has both hydrophilic and hydrophobic fragments,and self-assembles into spherical micelles when stirred in a mixture of aqueous and oil phases.and the spherical micelles are formed by stirring in a mixed solution of the aqueous phase and the oil phase.Furthermore,we use the amphiphilic polymer to encapsulate the small molecular drug doxorubicin in the core hydrophobic region,so as to study its application prospects in traditional chemotherapeutic drug delivery system.The particle size of the Nano-polymer delivery system was determined by DLS within 200 nm,which accorded with the optimum size range reported in literature.The morphology of the nano-polymers observed by transmission electron microscopy(TEM)was spherical.The drug loading and encapsulation efficiency of the drug-loaded micelles were calculated using an ultraviolet spectrophotometer.The encapsulation efficiency of the drug delivery system of LVal-L-Val-PEG-NO-YC-1 encapsulating DOX was 43.6%,and the drug loading was 6.5%.Under normal physiological pH conditions,the release of doxorubicin is quite slow and the release rate is very low.Under slightly acidic conditions,the release of doxorubicin is quite rapid,and the final release rate is as high as 80% or more.In vitro cytotoxicity experiments,drugloaded L-Val-L-Val-PEG-NO-YC-1 showed good activity compared to other control groups.In vivo experiments showed that HepG2 had a good anti-tumor effect on nude mice.