| Cancer has been known as one of the most threating diseases in the world,which causes millions of deaths every year.Many efforts have been made to fight against cancer such as radiotherapy,surgical resection,and chemotherapy.Regarding the malignancies such as gastric,colonic and cervical cancers,surgical removal is the best choice when the tumor is at an early stage without metastasis.However,for the metastatic cancer,chemotherapy and radiotherapy are the choices for controlling disease progression.However,chemotherapy,which utilizes small chemical molecules to cure cancer,has been suffering from the following problems: a)most anticancer molecules are hydrophobic,resulting in poor bioavailability;b)the cytotoxicity is lack of selectivity,leading to adverse effects to the normal organs.To address these issues,drug delivery vehicles such as polymers,liposomes,nanoparticles were explored.Mesoporous silica nanoparticles(MSNs)has been extensively explored in diverse fields such as gas storage,separation,catalysis,chemical sensing,and drug delivery,owing to its highly ordered structures,large pore size,low relative density,high specific strength,high surface area,and good adsorbability.Different kinds of drug molecules such as doxorubicin,deferasirox,and 2,4-dichlorophenoxy acetic acid,have been encapsulated into the mesopores of mesoporous silica nanoparticles to improve the solubility and stability of the loaded drug and effectively decrease the side-effects.However,the clinical application of MSN-based drug delivery system is limited partly by the premature cargo release.Herein,we designed a smart polymer gatekeeper containing azobenzene moiety that is sensitive to low oxygen concentration(i.e.hypoxia)in tumor sites via bioreduction.The nano-sized mesoporous silica particles were successfully prepared via a soft-template method with a uniform transmission electron microscope(TEM)size at 45.1 ± 4.8 nm.The hydrodynamic size via dynamic light scattering(DLS)was three times larger than the TEM diameter,which was mainly due to the partial doublet formation in the fusion process.A photosensitizer,Ce6 was physically encapsulated with a high drug loading(4.7 ± 0.2%).Subsequently,poly(4,4’-azodianiline)(pDAB)was coated onto the surface of Ce6-loading MSNs by a one-pot synthesis process and an amphiphilic copolymer,Pluronic F68(F68)was further deposited on its exterior to ensure good affinity or dispersibility of MSN in water.TEM and DLS were used to characterize the morphology of drug-loading nanocarriers Ce6@MSN/pDAB/F68 which had a larger diameter than un-coated MSN both in TEM(58.1 ± 6.0 nm)and DLS(202.9 ± 9.1 nm).The successful drug loading and polymer coating were verified by different spectroscopy.Sodium dithionite,a chemical reductant,was used to mimic the hypoxia environment in vitro.In sodium dithionite aqueous solutions,pDAB decomposed and detached from the surface of MSN,and then initiated the release of cargo molecules.In order to detect the process of drug release,fluorescence resonance energy transfer(FRET)pair(Cou6 and Rho B)were physically co-encapsulated and the obtained nanocarrier showed significant FRET phenomenon under normoxia.Once the Cou6+Rho B@MSN/pDAB/F68 was in hypoxic condition,either in sodium dithionite aqueous solution or MCF-7 cells,FRET pair molecules were released,leading to FRET phenomenon diminishment.This indicated that the hypoxia-sensitive pDAB controlled the cargo release under low oxygen environment.In addition,cytotoxicity assay of free drug,blank nanocarrier MSN/pDAB/F68 and drug-loading nanocarrier Ce6@MSN/pDAB/F68 and Dox@MSN/pDAB/F68 in MCF-7 cells further proved the hypoxia-triggered cargo release.This work developed novel hypoxia-sensitive nanocarriers that hold promise in controlling the cargo release under low oxygen microenvironment. |
