| Chronic disease refers to the general term of diseases that do not constitute infection but have long-term accumulation to form disease morphological damage.The common chronic diseases mainly consist of tumors,diabetes,arthritis,skin diseases,obesity,cardiovascular and cerebrovascular diseases,chronic respiratory diseases,other chronic systemic diseases or other chronic organ diseases.Chronic diseases usually have a long course of disease,protracted disease,and complex etiology,which are difficult to cure at one time.Globally,the proportion of patients with chronic diseases is increasing year by year,causing great harm to lives and economic losses.However,the current conventional oral administration and injection administration have certain limitations,which cannot meet the needs of daily treatment of extensive chronic diseases.Therefore,in this study,we used nanotechnology to prepare model drugs into nanoparticles suitable for transdermal drug delivery,which can meet the needs of transdermal drug delivery and the treatment characteristics of specific diseases,such as chronic wounds,tumors,and chronic pain.The main research results were as follows:(1)A chitosan-shellac sponge wound dressing based on bioadhesion design micelles was established for skin delivery of Asiaticoside to promote chronic wound healing.Chronic wound is a kind of complex,long duration,difficult to heal spontaneously.It can be life-threatening if left untreated.At present,wound dressings are commonly used in clinical practice to treat it.The chronic wound dressing can keep the microenvironment of the wound moist,prevent and treat infection,and reduce secondary injury caused by friction between the wound and the contact.In this study,we developed a chitosan-shellac based sponge scaffold loaded with Asiaticoside for chronic wound treatment.Chitosan and shellac were crosslinked to form a sponge scaffold with high porosity,low density,good water absorption and water retention,and ideal mechanical strength.Asiaticoside was prepared into micelles to greatly improve the solubility,and was loaded into chitosan-shellac based sponge scaffolds for evaluation of in vitro and in vivo antibacterial activity and promoting chronic wound repair activity.The results showed that the solubility of Asiaticoside in the micelles was more than 5mg/mL.After being loaded into the chitosan-shellac sponge scaffold,Asiaticoside had good release characteristics,showed obvious antibacterial activity in vivo and in vitro,and had a good effect on promoting cell proliferation.The application of Asiaticoside micellia-chitosan-shellac based sponge scaffolds in diabetic wound and pressure sore models has rapidly played the therapeutic role of hemostasis,antibacterial and promoted wound healing.These results suggested that Asiaticoside micellia-chitosan-shellac based sponge scaffolds have the possibility of becoming a good dressing for treatment of chronic wounds.(2)A simply prepared active targeted needle-free injection system responsive to the subcutaneous melanoma microenvironment was developed to treat melanoma in situ.Melanoma is a serious and deadly tumor with rising incidence worldwide,which accounts for just 3%of skin cancer deaths but contributes more than two-thirds of skin cancer deaths.Currently,surgery is still a treatment option for melanoma,especially early melanoma,but with limited effectiveness for metastatic melanoma and advanced melanoma.Chemotherapy,radiotherapy,targeted therapy and immunotherapy are commonly used to treat metastatic melanoma and advanced melanoma.Paclitaxel(PTX)is a chemotherapy drug that has been used for more than decades to treat severe or metastatic melanoma.In this study,we developed a simply prepared and effectively targeted needle-free injectable formulation containing PTX for the treatment of in situ melanoma.We used dipotassium glycyrrhizinate(DG)modified with folic acid(FA)and Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(Soluplus(?))to conduct a cocktail micelle(PTX@Soluplus/DG-pp-FA)to develop an intelligent drug delivery system that could actively target melanoma and undergo responsive changes in the microenvironment at the tumor site to release drugs.The PTX@Soluplus/DG-pp-FA micelles were globular,which greatly improved the solubility of PTX,which is 100 times that of free PTX,the solution.The results showed that the prescription-optimized PTX@Soluplus/DG-pp-FA micelles were spherical,which greatly improved the solubility of PTX,and was 100 times that of free PTX solution.PTX@Soluplus/DG-pp-FA has good rheology,which is conducive to the construction of needle-free injection drug delivery system(NF#PTX@Soluplus/DG-pp-FA).In vivo distribution results showed that PTX@FA-pp-DG-NF needleless injection administration had more PTX accumulation at the tumor site than intravenous administration,which due to the environmental responsiveness of Soluplus and the presence of DG.The pharmacodynamic results showed that NF#PTX@Soluplus/DG-pp-FA significantly improved the efficacy of PTX in the treatment of melanoma,and prolonged the survival period of the tumor-bearing mice.These results suggested that NF#PTX@Soluplus/DG-pp-FA we prepared has a great potential in building a multifunctional platform for PTX drug delivery.(3)A microneedle-mediated functional liposome membrane fusion exosome for delivery of ciconopeptide for central nervous analgesia research was constructed.Chronic pain is a widespread public and physical health crisis and a serious public health problem with a very high prevalence rate and heavy burden on society.Chronic pain is pain that takes longer than normal tissue healing time,has no apparent biological value,and is an unpleasant sensation and emotional experience associated with actual or potential tissue damage.Classifying it as injurious,neurotic,or combined based on history and examination presents a huge challenge for physicians.Ziconotide(ZIC)is an N-type calcium channel antagonist that can be used to treat severe chronic pain that is difficult to tolerate,or that does not respond well to other medications,such as intravaginal morphine and systemic analgesics.Intrathecal injection is the only way to administer ZIC due to it can only act in the brain and cerebrospinal fluid.In this study,Borneol(BOR)modified liposomes(LIPs)were fused with exosomes derived from mesenchymal stem cells(MSCs),and ZIC was loaded to prepare microneedles(MN#ZIC@MSCEXO/LIP-BOR MNs)to improve the efficiency of ZIC crossing the blood-brain barrier.The sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of neurogenic inflammatory pain induced by peripheral nerve injury,diabetic neuropathic pain,chemotherapy pain,and ultraviolet-B(UV-B)radiation to evaluate the local analgesic effect of MN#ZIC@MSCEXO/LIP-BOR MNs.The BOR modified LIPs loaded with ZIC(ZIC@LIP-BOR)are spherical or nearly spherical with a particle size of about 95 nm and a Zeta potential of-7.8 mV.After fusion with MSC exosomes,the particle size of ZIC@MSCEXO/LIP-BOR increased to 175 nm and the Zeta potential increased to-3.8 mV.Nano-MNs constructed based on BOR modified LIPs have good mechanical properties and can effectively penetrate the skin to release drugs.Analgesic experiments showed that ZIC had significant analgesic effect in different pain mouse models.In conclusion,the MN#ZIC@MSCEXO/LIP-BOR MNs constructed in this study provide a safe and effective delivery pathway for the treatment of chronic pain,and has great potential for the clinical application of ZIC.In summary,we have used nano-technology to prepare typical therapeutic drugs for specific disease treatment with insoluble or structural problems into nano-drug delivery systems suitable for the treatment of corresponding diseases to solve the disadvantages of traditional drug delivery difficulties or low compliance.With the means of skin delivery and transdermal delivery,it provides a new comparative approach for the clinical treatment of chronic diseases,a new way for the clinical application of nano-formulation technology,skin delivery and transdermal delivery,and provides new ideas and technical support for the research and development of new preparations. |
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