Based on a recent report concerning endogenous agents(i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like prot...Based on a recent report concerning endogenous agents(i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein(ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide(Nap FFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate(Dexp) to generate a Nap FFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery.The Nap FFKKFKLKL/Dexp hydrogel formed instantly after the complexation of Nap FFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy(TEM), fluorescent spectrum, circular dichroism(CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release.Following a single intravitreal injection, the proposed Nap FFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis(EAU) rat model,we demonstrated that the resulting Nap FFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting Nap FFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders(i.e., uveitis).展开更多
Background:Spinal cord injury(SCI),which often results from traumatic incidents,leads to neural damage and impaired sensory and motor functions and may pose a serious threat to life.Secondary injury mechanisms caused ...Background:Spinal cord injury(SCI),which often results from traumatic incidents,leads to neural damage and impaired sensory and motor functions and may pose a serious threat to life.Secondary injury mechanisms caused by persistent inflammation disrupt the local microenvironment,causing neuronal cell death and hindering neural regeneration.This study used a chitosan-citric acid(CS-CA)hydrogel as a carrier for Catalpol(CAT-CS-CA),which was directly applied to the injury site to promote SCI repair.Methods:CAT-CS-CA and CS-CA hydrogels were characterized and implanted into rat SCI models.Fifty-four male Sprague-Dawley rats(230-250 g)rats were involved in the experiment.Six rats were randomly divided into two groups(n=3 per group)for in vivo degradation of hydrogels.Forty-eight rats were randomly assigned into four groups(n=12)using a randomization protocol:sham operation group(laminectomy only),SCI group,CS-CA hydrogel group,and CAT-CS-CA hydrogel group.From each group,3 rats were randomly selected for serum and spinal cord tissue extraction,followed by ELISA and RT-qPCR assays to determine the expression levels of various inflammatory factors(IL-1β,IL-6,TNF-α,and IL-10).Another 3 randomly selected rats were used for the evaluation of hindlimb motor function.The remaining 6 rats in each group were used to detect the expression of neuronal nuclei(NeuN),βIII-tubulin(Tuj1),glial fibrillary acidic protein(GFAP),and macrophage polarization(M1/M2 markers).Results:The CAT-CS-CA hydrogel retains CS-CA hydrogel's advantages and gains enhanced neuroprotective and anti-inflammatory abilities.The implantation of CAT-CS-CA into injured rat spinal cords enhanced neuronal survival,stimulated axonal regeneration,and significantly suppressed glial proliferation at the injury site.In addition,it promoted macrophage polarization to the M2 phenotype and substantially enhanced hindlimb motor function in rats with SCI.Conclusion:CAT-CS-CA hydrogel promotes neuronal survival,suppresses glial scarring,and improves motor function,offering a promising strategy for SCI repair.展开更多
Boosting transcorneal permeability and pharmacological activity of drug poses a great challenge in the field of ocular drug delivery.In the present study,we propose a drug-peptide supramolecular hydrogel based on anti...Boosting transcorneal permeability and pharmacological activity of drug poses a great challenge in the field of ocular drug delivery.In the present study,we propose a drug-peptide supramolecular hydrogel based on anti-inflammatory drug,dexamethasone(Dex),and Arg-Gly-Asp(RGD)motif for boosting transcorneal permeability and pharmacological activity via the ligand-receptor interaction.The drug-peptide(Dex-SA-RGD/RGE)supramolecular hydrogel comprised of uniform nanotube architecture formed spontaneously in phosphate buffered saline(PBS,pH=7.4)without external stimuli.Upon storage at 4℃,25℃,and 37℃ for 70 days,Dex-SA-RGD in hydrogel did not undergo significant hydrolysis,suggesting great long-term stability.In comparison to Dex-SA-RGE,Dex-SA-RGD exhibited a more potent in vitro anti-inflammatory efficacy in lipopolysaccharide(LPS)-activated RAW 264.7 macrophages via the inhibition of nuclear factorкB(NF-κB)signal pathway.More importantly,using drug-peptide supramolecular hydrogel labeled with 7-nitro-2,1,3-benzoxadiazole(NBD),the Dex-SA-K(NBD)RGD showed increased performance in terms of integrin targeting and cellular uptake compared to Dex-SA-K(NBD)RGE,as revealed by cellular uptake assay.On topical instillation in rabbit’s eye,the proposed Dex-SA-K(NBD)RGD could effectively enhance the transcorneal distribution and permeability with respect to the Dex-SA-K(NBD)RGE.Overall,our findings demonstrate the performance of the ligand-receptor interaction for boosting transcorneal permeability and pharmacological activity of drug.展开更多
基金supported by the Zhejiang Provincial Natural Science Foundation of China (No. LR18H300002)the National Natural Science Foundation of China (Nos. 31671022, 81971732)。
文摘Based on a recent report concerning endogenous agents(i.e., pyridoxal phosphate, adenosine triphosphate, adenosine monophosphate, folinic acid) that modulate the oligomerization of apoptosis-associated speck-like protein(ASC) via the peptide epitope of KKFKLKL, we rationally designed and synthesized a nonapeptide(Nap FFKKFKLKL), which can co-assemble with dexamethasone sodium phosphate(Dexp) to generate a Nap FFKKFKLKL/Dexp supramolecular hydrogel for ocular drug delivery.The Nap FFKKFKLKL/Dexp hydrogel formed instantly after the complexation of Nap FFKKFKLKL with Dexp in aqueous solution. The formed supramolecular hydrogels were thoroughly characterized by transmission electron microscopy(TEM), fluorescent spectrum, circular dichroism(CD) spectra and rheology. The peptide concentration significantly affected the in vitro release behavior of Dexp from the supramolecular hydrogel, and the higher peptide concentration resulted in the slower drug release.Following a single intravitreal injection, the proposed Nap FFKKFKLKL/Dexp hydrogel displayed good intraocular biocompatibility without having an adverse impact on the retinal architecture and eyesight functions during one month of follow-up. Using an experimental autoimmune uveitis(EAU) rat model,we demonstrated that the resulting Nap FFKKFKLKL/Dexp hydrogel had potent capacity to alleviate the intraocular inflammation and retain the morphology of retinal architecture. Overall, the resulting Nap FFKKFKLKL/Dexp hydrogel may be a promising drug carrier system to treat various posterior disorders(i.e., uveitis).
基金supported by the Medicine health science and technology development program of Shandong Province(202403070969)。
文摘Background:Spinal cord injury(SCI),which often results from traumatic incidents,leads to neural damage and impaired sensory and motor functions and may pose a serious threat to life.Secondary injury mechanisms caused by persistent inflammation disrupt the local microenvironment,causing neuronal cell death and hindering neural regeneration.This study used a chitosan-citric acid(CS-CA)hydrogel as a carrier for Catalpol(CAT-CS-CA),which was directly applied to the injury site to promote SCI repair.Methods:CAT-CS-CA and CS-CA hydrogels were characterized and implanted into rat SCI models.Fifty-four male Sprague-Dawley rats(230-250 g)rats were involved in the experiment.Six rats were randomly divided into two groups(n=3 per group)for in vivo degradation of hydrogels.Forty-eight rats were randomly assigned into four groups(n=12)using a randomization protocol:sham operation group(laminectomy only),SCI group,CS-CA hydrogel group,and CAT-CS-CA hydrogel group.From each group,3 rats were randomly selected for serum and spinal cord tissue extraction,followed by ELISA and RT-qPCR assays to determine the expression levels of various inflammatory factors(IL-1β,IL-6,TNF-α,and IL-10).Another 3 randomly selected rats were used for the evaluation of hindlimb motor function.The remaining 6 rats in each group were used to detect the expression of neuronal nuclei(NeuN),βIII-tubulin(Tuj1),glial fibrillary acidic protein(GFAP),and macrophage polarization(M1/M2 markers).Results:The CAT-CS-CA hydrogel retains CS-CA hydrogel's advantages and gains enhanced neuroprotective and anti-inflammatory abilities.The implantation of CAT-CS-CA into injured rat spinal cords enhanced neuronal survival,stimulated axonal regeneration,and significantly suppressed glial proliferation at the injury site.In addition,it promoted macrophage polarization to the M2 phenotype and substantially enhanced hindlimb motor function in rats with SCI.Conclusion:CAT-CS-CA hydrogel promotes neuronal survival,suppresses glial scarring,and improves motor function,offering a promising strategy for SCI repair.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(Grant No.LR18H300002 and LQ20C080002)the National Natural Science Foundation of China(Grant No.81971732).
文摘Boosting transcorneal permeability and pharmacological activity of drug poses a great challenge in the field of ocular drug delivery.In the present study,we propose a drug-peptide supramolecular hydrogel based on anti-inflammatory drug,dexamethasone(Dex),and Arg-Gly-Asp(RGD)motif for boosting transcorneal permeability and pharmacological activity via the ligand-receptor interaction.The drug-peptide(Dex-SA-RGD/RGE)supramolecular hydrogel comprised of uniform nanotube architecture formed spontaneously in phosphate buffered saline(PBS,pH=7.4)without external stimuli.Upon storage at 4℃,25℃,and 37℃ for 70 days,Dex-SA-RGD in hydrogel did not undergo significant hydrolysis,suggesting great long-term stability.In comparison to Dex-SA-RGE,Dex-SA-RGD exhibited a more potent in vitro anti-inflammatory efficacy in lipopolysaccharide(LPS)-activated RAW 264.7 macrophages via the inhibition of nuclear factorкB(NF-κB)signal pathway.More importantly,using drug-peptide supramolecular hydrogel labeled with 7-nitro-2,1,3-benzoxadiazole(NBD),the Dex-SA-K(NBD)RGD showed increased performance in terms of integrin targeting and cellular uptake compared to Dex-SA-K(NBD)RGE,as revealed by cellular uptake assay.On topical instillation in rabbit’s eye,the proposed Dex-SA-K(NBD)RGD could effectively enhance the transcorneal distribution and permeability with respect to the Dex-SA-K(NBD)RGE.Overall,our findings demonstrate the performance of the ligand-receptor interaction for boosting transcorneal permeability and pharmacological activity of drug.
