Study Of Synthesis And Renal Disease Therapy Of Polymer Porous Nanomembrane And Mesoscale Nanoparticles

Recent years,self-assembly has been drawn extensive attention owning to their great potential for creating new materials with special structure and function.In biomedical field,self-assembled nanomaterials have been widely applied in biological imaging and diagnosis,drug delivery,biosensing,tissue engineering and photothermal therapy by taking advantage of their excellent biocompatibility,unique and tailorable physicochemical properties and surface functionalization.Compared with other nanomaterials,Polymer self-assembled nanomaterials possess a broader application prospect in biomedical area for their special biodegradability and design diversity of polymer molecules with different structures and functional groups.With the increase of environmental pollution,life and work pressures and bad habits?e.g.,obesity and smoking?,the ever-increasing global incidence and mortality of kidney diseases severely threaten the public health.The fundamental causes of nephropathy are damage of glomeruli and renal tubules,especially the glomerular filtration membrane?GFM?and proximal tubular epithelial cells?PTECs?.Nowadays,the mainly therapy for renal diseases in clinic is pharmacological intervention to improve hemodynamics and fluid state,control cardiorenal or hepatorenal syndrome,inhibit renin-angiotensin-aldosterone system,reduce hypertension and control acid-base balance or uric acid,etc.These traditional treatment,however,can only delay progression of kidney diseases rather than repair the damaged GFM and renal tubules.Moreover,most of these therapeutic agents are toxic and renal non-specificity,resulting in repetitiousness and resistance to drugs.Thus,it is of great significance to develop drugs or treatments to repair the damaged GFM or renal tubules.Based on current research status of kidney disease treatment and biomedical application of polymer self-assembly,we carried out the research in term of the repairment of damaged GFM and PTECs.The repair of injured GFM by polymer porous self-assembled nanomembranes?PSANMs?and therapy of damaged renal tubules by PTECs-targeted polymer mesoscale nanoparticles?MNPs?were investigated.PSANMs with average thickness and pore diameter of ca.10-12 and 20–24 nm were prepared by employing carboxyl-terminated 16-armed poly?l-lactic acid?(Gn-?COOH?_x,n=1-5,x=16×2^n-1)as self-assembly units.With an increase of carboxyl density of Gn-?COOH?_x,the thickness and pore diameter of PSANMs decreased while the carboxyl density on their surfaces increased.Moreover,when the concentration of Gn-?COOH?_x?10-fold?and solvent volume ratio?2-fold?were increased,the self-assembled morphology was changed into nanofiber microspheres from PSANMs.An emulsification-induced programmable controlled self-assembly mechanism for the preparation of PSANMs was proposed through an assay of the self-assembly process.Additionally,the morphology of PSANMs were highly associated with molecular structure of poly?l-lactic acid?,Gn-?COOH?_x concentration and stirring speed.By adjusting these parameters,the PSANMs structure were finally optimized.The PSANMs were successfully grafted with water-soluble polyethylene glycol?PEG?by amide reaction between carboxyl and amino,and hydrophilic,anti-biofouling and anti-thrombotic PSANMs-g-PEG were obtained.Studies found that the porous membrane structure of PSANMs were not associated with PEGylation.When the PEG density or length increased,the thickness of PSANMs-g-PEG slightly increased while their pore diameter mildly decreased.Importantly,the hydrophilic and anti-biofouling performance of PSANMs-g-PEG were effectively improved with an increase of PEG density and length??5kDa?.Moreover,increasing the density of PEG 5 kDa effectively enhanced the anti-thrombotic ability of PSANMs-g-PEG 5 kDa,which was confirmed by the increased blood coagulation time?R-time?and reduced platelet aggregation and activation.Additionally,PSANM₂₅₆-g-PEG 5 kDa?PEG density was 0.0446 chains/nm²?showed the best anti-biofouling?83%reduction in protein adsorption?and anti-thrombotic performance?R-time was 5.37 min?.Using amide reaction between carboxyl and amino,the PSANM₂₅₆-g-PEG 5 kDa were successfully modified with glomerulus-specific antibody?Ab?,which effectively improved the cellular intake efficiency of PSANM₂₅₆-g-PEG-Ab by podocytes and endowed them with kidney-targeted property.when injected into the blood of adriamycin?ADR?nephropathy mice by intravenous injection,PSANM₂₅₆-g-PEG-Ab would spread over the damaged GFM via the recognition reaction of antigen-antibody and prevent protein through GFM.Our results showed that serum creatinine?SCr,1.6-fold?and urine protein?2.0-fold?were effectively reduced when the ADR mice were intervened by PSANM₂₅₆-g-PEG-Ab.Moreover,the histopathological lesion of injured GFM were significantly alleviated.In comparison with traditional treatment,PSANM₂₅₆-g-PEG-Ab directly repaired the damaged GFM,making it a potential drug for complete cure of early-or middle-stage kidney diseases.Amphiphilic?D,L-lactate-co-glycolic acid?-b-polyethylene glycol?PLGA-b-mPEG?copolymer was synthesized by amide reaction of carboxyl with amino.Uniform-sized,biocompatible and PTECs-targeted TP-encapsulated MNPs?TP-MNPs?with high-efficiency treatment for renal ischaemia-reperfusion injury?IRI?were fabricated through a simple nanoprecipitation method.These TP-MNPs exhibited excellent kidney-targeted capacity with long renal retention time?7 days?.By taking advantage of encapsulation strategy,TP-MNPs effectively reduced the cytotoxicity,hepatotoxicity,reproductive toxicity and immune toxicity of TP.Moreover,only low dosage of TP-MNPs?equivalent to 0.01 mg/kg TP?can significantly reduce the renal tubule pathological damage?3.2-fold?,SCr?5.9-fold?,blood urea nitrogen?2.0-fold?and PTECs apoptosis of renal ischemia-reperfusion?IRI?mice,while TP with the same dose were completely ineffective.Compared with kidney-targeted drug delivery system with the small-size,this drug delivery system greatly simplifies the preparation and purification process and enhances the therapeutic efficiency,which may pave an avenue for designing a new therapeutic strategy for renal diseases.