Use Of Solanesol Derivative Micelles Containing Maleic Acid Amide Bond In Drug Delivery

Compared with normal tissues,the acid extracellular microenvironment with pH of 6.5-7.0 will be formed in tumor site due to abnormal metabolism of tumor cells,which provides a unique condition for the design of intelligent nano drug delivery system,that is,tumor cells have higher acidity in the extracellular space of low perfusion area compared with surrounding normal tissues.Therefore,pH sensitive nano drug delivery system has been widely used in cancer treatment research.Maleic acid amide bond is formed by simple reaction of maleic anhydride and amino group.Under weak acid condition,maleic acid amide bond will break and decompose into maleic anhydride and amino group.It can be used as the response site of pH sensitive nano micelle delivery system by using the weak acid cleavage characteristics of maleic acid amide bond.Based on this,a series of drug delivery systems with pH sensitive maleic acid amide bond were designed and studied in this paper.Firstly,maleic anhydride terminated polyethylene glycol monomethyl ether(CDM-PEG)was synthesized as the hydrophilic segment of micelles;then solanesol with natural biological activity and strong hydrophobicity was modified as the hydrophobic segment(SOL-NH)of the micelles,and the amphiphilic micelle material SOL-NH-CDM-PEG containing maleic acid amide bond was successfully prepared through the synthesis reaction.The maleic acid amide bond in the micelles can be cleaved under weak acid conditions to realize pH responsive drug delivery in the nano drug delivery system.The particle size,morphology,drug loading and stability of polymer micelles were characterized by laser particle size analyzer,nuclear magnetic resonance spectrometer,high resolution transmission electron microscope and fluorescence spectrophotometer.The results showed that the particle size and PDI of polymer nano micelles were small,and the polymer micelles could exist stably;the drug loading of SOL-NH-CDM-PEG micelles was about 6%.TEM results showed that the micelles were spherical in structure.In vitro drug release studies showed that the polymer SOL-NH-CDM-PEG(DOX)loaded micelles exhibited a pH dependent release behavior to doxorubicin.The cumulative release of doxorubicin in 24 h was up to 80% under weak acid condition,and less than 50% in 24 h at pH = 7.4.In the control group,the release of SOL-NH-NHS-PEG(DOX)micelles was slow at different pH conditions,and the release rate and total release amount were not significantly different.The cumulative release amount was about 50% in 72 h.Compared with SOL-NH-NHS-PEG(DOX)loaded micelles,the experimental group SOL-NH-CDM-PEG(DOX)micelles had stronger tumor cell inhibitory effect,but still weaker than that of free doxorubicin,which may be due to the fact that free doxorubicin is easier to enter cells.The anti-tumor effect evaluation in vivo showed that SOL-NH-CDM-PEG(DOX)containing maleic acid amide bond had the best antitumor effect,and the comparison of the effects of drug loaded micelles and free drug doxorubicin on the health status of mice showed that the drug loaded micelles significantly reduced the toxicity and side effects of free doxorubicin.