Study On The Preparation And Properties Of A Mesoporous Silica Nanoparticles Active Targeting Drug Delivery System

The interaction of factors that lead to tumor is a multi-step,multi-stage,and a complex process.Compared with one receptor mediated drug deivery system,the dual and multi-receptor mediated drug delivery system have a significant improvement in targeting cancer cells.Therefore,mesoporous silica nanoparticles（MSNs）modified with hyaluronic acid（HA）and RGD peptide（MSNs-HA-RGD）were developed and characterized by TEM,DLS,SAXRD,nitrogen adsorption-desorption analysis,FT-IR,UV-vis and ¹³C NMR in the present study.Chlorambucil（CHL）,also known as leukeran,is a nitrogen mustard and can cause many serious side effects.The whole blood drop may happen when use a large doses of continuous medication.Furthermore,it readily gets multidrug resistance（MDR）.The CHL was loaded in the MSNs-HA-RGD nanoparticle,resulting in a dual-receptor mediated active targeting drug delivery system CHL/MSNs-HA-RGD.It is expected that the CHL/MSNs-HA-RGD nanoparticles can overcome the CHL’s drawbacks in clical applications and may be a promising candidate for cancer treatments.A nano-carrier MSNs without CTAB was prepared in a near neutral condition,and then was functionalized with amino by a post-grafting method to afford as MSNs-NH₂.In order to investigated the cellular uptake of MSNs,the fluorophore Rhodamine B was used to label MSNs-NH₂ and finally gave MSNs-RhB.Combining the complexity of cancer treatments,the hyaluronic acid and RGD peptide were further used to conjugated with MSNs-NH₂ to improve the tumor cell tareting,the obtained sample was referred to as MSNs-HA-RGD.A RhB labeled MSNs-HA and MSNs-HA-RGD,which used for monitoring the distribution of nanoparticles in the cells,were synthesized by conjugating the Rhodamine B on the outside surface of MSNs-NH₂,and the sample was referred to as MSNs-HA-RhB and MSNs-HA-RGD-RhB,respectively.The CHL,an anticancer drug,was loaded into the different initial carrier to achieve an optimal drug loading efficiency and encapsulation efficiency.The results show that the optimal formulation was prepared by loading CHL in the stage of MSNs-NH₂,and then in vitro CHL release studies were carried out in the text.Cytotoxicity of CHL-loaded MSNs,MSNs-HA,MSNs-HA-RGD,and cellular uptake of RhB-labeled CHL/MSNs,CHL/MSNs-HA,CHL/MSNs-HA-RGD were investigsted.Furthermore,receptorinhibitiononcellularuptakeof CHL/MSNs-HA-RGD was further evaluated the the dual-receptor mediated endocytosis pathway.The Rhodamine B was further chosen as a model drug to afford as RhB/MSNs-HA-RGD.The cellular uptake of CHL from CHL/MSNs-HA-RGD was estimateded by the fluorescence signals of RhB.The results showed that MSNs-HA-RGD nanoparticles had a uniform particle size（172.5±10 nm）,ideal monodispersity.CHL was chosen as a model drug to investigate the drug loading,and the loading efficiency and encapsulation efficiency of CHL/MSNs-HA-RGD was up to 21.07%and 70.23%,indicating that MSNs-HA-RGD nanopartices had an high loading capacity of drug.In vitro drug release property exhibited that CHL/MSNs-HA-RGD nanoparticles had a pH-sensitive and enzyme-sensitive drug controlled release property.The cellular experiment showed that dual-receptor mediated active targeting drug delivery system（CHL/MSNs-HA-RGD）had an ideal dual-receptor mediated endocytosis pathway and could be significantly internalized into cancer cells than the MSNs modified with one receptor,thus improving the effective therapeutic concentrations of CHL in cancer focus.Moreover,CHL/MSNs-HA-RGD nanoparticles had a strongly higher cytotoxicity against cancer cells than against non-cancer cells.The results showed that the dual-receptor mediated active targeting drug delivery system（CHL/MSNs-HA-RGD）would be a promising targeting drug delivery system for improving the therapeutic index of CHL.