Study On A Nano Drug Delivery For Targeting The Tumor Metastatic Lymph Node Based On The Enzyme-substrate Specificity Interaction

Lymphatic metastasis is one of the main tumor metastasis.Lymphatic metastasis seriously affects the cure rate and survival of cancer patients.Therefore,according to the physiological characteristics of tumor lymphatic metastasis,it has theoretical significance and practical value to create new drug delivery system and specially target drugs or imaging agents to metastatic lymph nodes.This paper constructs LMWH-Lips for the first time to target metastatic lymph node based on the HPA-LMWH interaction mechanism,and deeply explore the targeting capabilities,targeting mechanisms,imaging and therapeutic effects.At first,HA and HEP,two kinds of macromolecular polysaccharide,were selected as specific ligand to combine lymphatic metastasis-associated protein receptor and enzyme.HA-Lips/DTX and HEP-Lips/DTX were respectively constructed by electrostatic adsorption of HA and HEP on the surface of DTX liposome.Experimental results show that both liposomes with high encapsulation efficiency and good stability charged negatively and have 150-200nm particle size.Then,lymphatic metastatic tumor model is established by subcutaneous injection of Hela cells via left hind foot pad in nude mice.HA-Lips/DTX and HEP-Lips/DTX are subcutaneously injected and the metastatic lymph node targeting ability of HA-Lips/DTX and HEP-Lips/DTX are comprehensively evaluated by lymph node uptake,injection site retention and plasma-drug concentration.We can see that HEP-Lips/DTX has better metastatic lymph node targeting ability by comparison.In addition,the different molecular weight HEP and LMWH modified liposomes are compared by lymph node uptake and the preferred LMWH-Lips are further studies.LMWH-Lips respectively load Cy7 or DTX to evaluate the ability of near-infrared in-vivo imaging and chemotherapeutic drugs targeting.It implies that LMWH-Lips can significantly improve the imaging level and chemotherapy drugs content in lymph node metastasis.With different concentrations and expression levels of HPA existing,the effect of enzyme-substrate interactions influence(HPA-LMWH)on the metastatic lymph node targeting ability of LMWH-Lips are examined,indicating HPA-LMWH effect can degrade LMWH coating layer on the liposome surface,increasing lymph nodes uptake,prolonging residence time and improving tumor cellular uptake.Finally,in vivo distribution and efficacy of LMWH-Lips/DTX are studied.The results show that LMWH-Lips/DTX can improve the efficacy docetaxel for metastatic tumor cells and t metastatic lymph nodes and reduce systemic toxicity.In summary,LMWH-Lips could be a promising drug delivery system for targeting tumor metastatic lymph nodes.