The Study Of Lactoferrin-modified Alginate-Based Nanogel-Thermoresponsive Hydrogel Controlled Release Of Icariin In The Treatment Of Parkinson’s Disease

Parkinson’s disease（PD）is the second largest neurodegenerative disease in the word.With the aging of the global population,the number of people over 60 years old in the word will reach 2 billion by 2050,an increase of 900 million from 2015,and the number of PD patients will certainly increase.Then the prevalence of people over the age of 60 will be as high as two-thirds,which is undoubtedly a new challenge to the global health system.At present,the main therapeutic drugs have many problems such as large side effects,poor targeting,and low bioavailability.By modifying the structure of the lead compound to adjust the lipid-water partition coefficient of the drug so that the drug can easily cross the blood-brain barrier,the design and preparation of advanced drug preparations is the main research direction of PD at present.According to the pathogenesis and characteristics of PD,the study selected icariin,a traditional Chinese medicine ingredient with good anti-inflammatory and antioxidant activity,as a candidate drug.A lactoferrin-modified alginate brain targeting agent（SA-Lf-NGTH@ICAR）based on receptor-ligand interaction is proposed,which aimed to transport icariin into the brain efficiently and accurately,and released the drug to improve the effect of treatment.First,sodium alginate was modified with lactoferrin to prepare zinc alginate nanogels as the drug release storehouse of icariin.Then,the nanogel drug delivery system was loaded into the temperature-sensitive poloxamer system to prepare an advanced formulation that is easy to be administered nasally for the treatment of PD.The fourier transform infrared spectroscopy,ultraviolet spectroscopy,X-ray electron spectroscopy and particle size results showed that lactoferrin was successfully modified on alginic acid macromolecules.The particle size of the nanogel was 77.95 nm,the zeta potential was-8.23 m V,and the drug loading rate was 2.79%.The results of X-ray electron spectroscopy indicated that lactoferrin could be partially exposed on the surface of the nanogel,and zinc ions were not detected on the surface,which meant that it may be involved in the gelation inside the gel.At the same time,the drug release study was carried out in the nasal simulant,and the drug release profiles of nanogels conformed to the first-order release,the equation was Y=9.14X^1/2-3.39（R2=0.9342）.The cumulative release rate was 60%,the release amount within 4 h is tiny,indicating that the loss caused by drug burst release in the nasal environment or in the transport environment was small.Therefore,it met the requirements of nasal administration for the treatment of PD.The biocompatibility of the nanogels was examined by in vitro experiments.When the gel concentration was as high as 2 mg/m L,the hemolysis rate was still lower than 5%,which was in line with the national requirements.The tissue distribution and brain targeting were examined by fluorescence measurement.The SA-Lf-NGTH@ICAR has a good effect of targeted aggregation in the brain.Parkinson’s model mice were established,and the therapeutic effect and mechanism of the nasally administered nanogel for treatment of PD were investigated through pharmacodynamics,pharmacology and other analyses.The results showed that SA-Lf-NGTH@ICAR could significantly improve the motor ability of PD mice,increase their desire to explore,and reduce the expression ofα-syn in the brain of model mice.The PCR results indicated that SA-Lf-NGTH@ICAR could regulate the level of oxidative stress and inflammation in the mouse brain.The above results indicate that SA-Lf-NGTH@ICAR can target drugs to the brain to exert anti-PD effect.