Development And Evaluation Of Lipid Coated Mesoporous Silica Nanoparticle As Drug Delivery System

Chemotherapy plays a key role in cancer treatment,but the lack of target specificity usually leads to severe side effects and suboptimal therapeutic efficacy.Numerous nano drug delivery systems have been developed to achieve tumor-targeted drug delivery via passive or active targeting mechanism.Mesoporous silica nanoparticle exhibited many advantages when being employed as drug delivery systems,1)large surface area and pore volume which could achieve high loading capacity;2)adjustable particle and pore size which could maintain the the drug molecules stably dispersed within the pore channel;3)physi-chemically stable which could preserve their structure after administration.However,there are still many existing challenges for unmodified MSNs when used as the delivery vehicles for anticancer drugs.Since the pore channel are not blocked,MSNs may suffer from premature drug release before reaching the specific site which may cause additional side effects and lead to decreased amount of drug arrived at the tumor site and compromise the final therapeutic outcome.Moreover,MSNs tend to absorb proteins in the serum and aggregate under high ionic strength which may lead to accelerated clearance from circulation and failure to accucumulate at the tumor site via EPR effect.To overcome the above challenges,two kinds of hybrid lipid MSNs drug delivery systems were developed by coating the MSNs with a lipid layer.It is expected that the lipid layer could act as a diffusion barrier to prevent premature drug release and improve the safty,dispersing stability of MSNs and therapeutic outcome of anticancer drug.An lipid coated MSNs drug delivery system(LMSNs)was first developed.Confocal laser scanning microscopy(CLSM),N2 absorption(BET)、Dynamic light scattering(DLS)and thermal gravimetric Analyzer(TGA)were conducted to confirm the lipid coating.And the results indicated that the lipid layer had been coated on MSNs with weight percentage of 30%.In order to test the integrity of the lipid layer,FEI Tecnai F20 cryo-TEM was employed to observe the LMSNs,there were MSNs fully covered by the lipid layer with thickness of about 4-5nm and there were still MSNs that were only partially covered by the lipid layer.When DOX was encapsulated into LMSNs,the obtained LMSNs-DOX had uniform particle size distribution of 305±16nm and a loading efficiency of 16%.To investigate whether the lipid layer could prevent premature drug release,the in vitro release study of LMSNs-DOX was conducted.The release profile showed that the cumulative relase of MSNs-DOX at 24h under pH 7.4 were 22%,while the cumulative release of LMSNs-DOX decreased to 8%,indicating that the lipid layer could provide diffusion hindrance to the release of DOX.In order to further investigate the effect of lipid coating on the property of MSNs,the safty,dispersing stability and and cellular uptake efficiency of MSNs and LMSNs were compared.The result of hemolysis showed that MSNs were hemolytic within the concentration range from 400-1500μg·mL-1.While LMSNs did not induce hemolysis under the same concentration.Compared with MSNs,the toxicity of LMSNs greatly decreased and the dispersing stability significantly improved.MCF-7 human breast cancer cell line were selected to investigate the cellular uptake of MSNs and LMSNs.It was shown that LMSNs had higher cellular uptake efficiency compared to MSNs.After loaded with DOX,compared with DOX-Sol and MSNs-DOX,the LMSNs-DOX exhibited higher toxicity,and the IC50 valuedecreased by 2.2 and 1.3times compared to DOX-Sol and MSNs-DOX.The second type of carrier is a TPGS hybrid lipid layer coated mesoporous silica used for redox responsive drug release.And the mechanism is that there is a huge difference in redox potential between intracellular and extracellular environment,so it can be used as a trigger for redox responsive drug release.In our study,MSNs were firstly modified with a layer of hydrophobic chains via the disulfide bond.After introducing the TPGS and phospholipids with specific ratio,they will self-assemble into a TPGS hybrid lipid layer around MSNs via the hydrophobic interaction.A variety of characterizations confirmed the capping of the TPGS containing lipid layer on MSNs.The obtained LTMSNs had desired particle size and surface charge to be used in vivo and exhibited excellent dispersing stability.The in vitro release profile showed that the TPGS containing lipid layer could effectively prevent the premature release of DOX in normal physiological environment.Only with the presence of GSH at high concentration,DOX was allowed to release after the cleavage of disulfide bond and detachment of TPGS containing lipid layer.Due to the pH dependent interaction between DOX and MSNs,the release percentage of DOX under pH 5.0 was higher than that under pH 7.4.So the LTMSNs-DOX demonstrated pH and redox dual responsive release behavior.It was also been found that the presence of TPGS containing lipid layer could also improve the biocompatibility and stability of the particle,and reduce the non-specific protein absorption probably due to the hydrophilic PEG chains from TPGS.Moreover,the LTMSNs showed enhanced cellular uptake efficiency and great capacity to inhibit the efflux effect of DOX by P-gp,which consequently promoted the cytotoxic effect of DOX towards the drug resistant cancer cells.the in vivo study showed that LTMSNs achieved higher accumulation at the tumor site compared with free DOX and MSNs-DOX.It also showed enhanced anti-tumor effect and reduced systemic side effect.The above experimental results indicated that the employment of phospholipids as diffusion barrier in both ways could improve the biocompatibility and stability of particles.The lipid layer facilitated the cellular uptake of the drug loaded particle and helped to prolong the circulation time of particle.Compared with the lipid bilayer prepared by liposome fusion,the TPGS containing lipid layer coated on MSNs through hydrophobic interaction seemed to have more complete coverage on MSNs and therefore better performance in preventing premature release of DOX.The prepared LTMSNs could realize pH and redox dual responsive release of DOX.It could also inhibit the efflux effect of P-gp and increase the distribution of drug at the tumor site.The strategy of using phospholipids to act as a diffusion barrier to prevent premature drug release as well as to improve the applicability of drug carrier in vivo has provided a valuable reference for the future design of drug delivery systems based on mesoporous silica.