Implications Of Functionalized Nanodrug Delivery Systems For Anti-Cancer Therapy

Nanoparticles drug delivery systems for therapeutic implications in cancer treatment are much warented as conventional chemotherapeutic approach has several drawbacks including,but not limited to,requiring high doses of anti-cancer drugs with low bioavailability and non-specific targeting.Nano-drug delivery platforms?NDDPs;with a metal core?have emerged as promising drug carrying vehicles in targeted anti-cancer therapy.Among wide range of inorganic agents,mesoporous silica nanoparticles?MSNs?and gold nanoparticles?AuNPs?bear huge potential for targeted anti-cancer therapy.Glycosaminoglycans?GAGs?are linear polysaccharides which can be used functionalize the chemotherapeutic drugs loaded inorganic NDDPs inorder to further improve the drug treatment effect by increasing drug stability and enhancing drug bioavailability.Hyaluronic acid?HA?,heprin?HP?and heparan sulfate?HS?are major GAGs are major types of GAGs.Firstly,a novel enzyme-responsive,multistage-targeted anticancer drug delivery system based on MSNs was developed possessing both CD44-targeting and mitochondrial-targeting properties.Triphenylphosphine?TPP?,a mitochondria-targeting compound,was grafted onto the surface of MSNs and Doxorubicin?DOX?was encapsulated into the pore of MSNs followed by capping with tumor-targeting molecules hyaluronic acid?HA?to form final nano-system?MSN-DPH?.In vitro results suggested that MSN-DPH preferentially taken up by cancer cells via CD44 receptor-mediated endocytosis.Moreover,MSN-DPH mainly accumulated in mitochondria owing to the mitochondrial-targeting ability of TPP.Degradation of HA by overexpressed hyaluronidase facilitated the release of DOX in cancer cells.Thus,MSN-DPH efficiently killed the cancer cells while exhibited much lower cytotoxicity to normal cells.Next,Au@MSNs nanoparticles were synthesized and functionalized by thiol?-SH?and GAGs?HA,HP,HS?.The Au@MSNs nanoparticles found to be spherical and uniform in size.The diameter of gold core was 22 nm whereas it was 88 nm for Au@MSNs.The hydrated particles size of Au@MSNs was about 395 nm as measured by Dynamic light scattering?DLS?.The particle size of Au@MSNs@HA is about 93+2 nm,that of Au@MSNs@HS is about 95+2 nm,and that of Au@MSNs@HP is about 95+3 nm.Further,the thiol-grafting rate on HA,HP and HS was 10.0%,58.10%and 17.99%,respectively.DOX was susessfully loaded on Au@MSNs@GAGs and drug release from Au@MSNs@GAGs tested in vitro.It was found that after 24 hours drug release was complete.The IC₅₀ values of Au@MSNs@HA found as 20 ug/ml?equivalent DOX concentration is 2.8 ug/ml?,Au@MSNs@HS as 5 ug/ml?equivalent DOX concentration is0.7 ug/ml?and Au@MSNs@HP as 15 ug/ml?equivalent DOX concentration is 2.1 ug/ml?.Further,Au@MSNs@GAGs showed synergestic photothermal effect combined with chemotherapeutic drug therapy.The survival rate of HepG2 cells reduced when irradiated with DOX-loaded Au@MSNs@GAGs and near infrared laser?2W/cm²?.MTT assay used to test the cytotoxicity of Au@MSNs@GAGs and findings verified that Au@MSNs@GAGs possessed good anticancer effect being less toxic to normal cells.Confocal laser scanning microscopy analysis revealed cellular uptake of Au@MSNs@GAGs by HepG2 cells.