Mesoporous Organosilica Based Multi Imaging Modalities Guided Enhanced Tumor Therapy

Traditional methods for cancer therapy have many limitations.For example,chemotherapy usually causes systemic toxicity,and radiotherapy relies on oxygen concentration,which is usually low in tumors.Compared with traditional methods,nanoplatforms provide considerable promise for cancer diagnosis and treatment,which can combine various imaging modalities with selectable therapeutic functionalities.The integration of imaging and therapeutic capabilities into single nanoplatforms,resulting in an approach termed "theranostics",has been realized and drawn increasing interest for drug delivery tracking,therapy response monitoring,and image-guided therapy.Mesoporous organosilica nanoparticle based theranostics have been widely developed because of their mono-dispersity,well-defined mesopores,large surface area,biodegradability,and good biocompatibility.We designed three mesoporous organosilica nanoparticle based theranostics and explore their applications in cancer diagnosis and therapy.1.Systematically engineered periodic mesoporous organosilica nanoparticles for cancer cell targeting imaging and enhanced chemotherapyA cancer cell targeting imaging and drug delivery system based on engineered thioether-bridged periodic mesoporous organosilica nanoparticles(PMOs)is presented.The PMOs are stably and selectively conjugated with near-infrared fluorescence(NIRF)dye Cyanine 5.5(Cy5.5)and anti-Her2 affibody on the outer surfaces to endow them with excellent NIRF imaging and cancer targeting properties.Also,taking the advantage of the thioether-group-incorporated mesopores,the release of chemotherapy drug doxorubicin(DOX)loaded in the PMOs is responsive to the tumor-related molecule glutathione(GSH).The drug release percentage reaches 84.8%in 10 mM of GSH solution within 24 h,which is more than two-fold higher than that without GSH.In addition,the drug release also exhibits pH-responsive,which reaches 53.6%at pH 5.0 and 31.7%at pH 7.4 within 24 h.Confocal laser scanning microscopy and flow cytometry analysis demonstrate that the PMOs-based theranostic platforms can efficiently target to and enter Her2 positive tumor cells.Thus,the smart imaging and drug delivery nanoplatforms induce high tumor cell growth inhibition.Meanwhile,the Cy5.5 conjugated PMOs perform great NIRF imaging ability,which could monitor the intracellular distribution,delivery and release of the chemotherapy drug.In addition,cell viability and histological assessments show the engineered PMOs have good biocompatibility,further encouraging the following biomedical applications.Over all,the systemically engineered PMOs can serve as a novel cancer cell targeting imaging and drug delivery platform with NIRF imaging,GSH and pH dual-responsive drug release,and high tumor cell targeting ability.2.Tri-stimuli-responsive biodegradable theranostics for mild hyperthermia enhanced chemotherapyThe combination of hyperthermia and chemotherapy is able to greatly enhance the treatment efficacy mainly due to the synergistic interactions between these two treatments.In this study,we propose a new concept of mild hyperthermia enhanced chemotherapy to explore and validate the synergistic mechanism in vitro and in vivo.To do this,a novel kind of biodegradable nanotheranostics based on copper sulfide doped periodic mesoporous organosilica nanoparticles(CuS@PMOs)was constructed via an in situ growth method for light-triggered mild hyperthermia and drug delivery.The as-prepared CuS@PMOs exhibit a high doxorubicin(DOX)loading capacity of 470 mg/g.The DOX release from CuS@PMOs can be precisely controlled by three stimuli,including intracellular glutathione(GSH),acidic environment in tumor cells,and external laser irradiation.Most intriguingly,mild hyperthermia induced by laser-irradiated CuS nanoparticles can dramatically improve the cell uptake of nanotheranostics both in vitro and in vivo,thus significantly enhancing the chemotherapeutic efficacy for complete tumor growth suppression without recurrence.Meanwhile,the fluorescence recovery following the DOX release can be used as an indicator to monitor the chemotherapeutic progress.3.Mild hyperthermia-activated perfluoropentane vaporization for hypoxia-specific oxygen-sensitized radiation enhancementHypoxia environment in tumors induces hypoxia-associated resistance of radiotherapy(RT).Perfluoropentane(PFP)has high affinity to oxygen,whose boiling point is around 40-50℃ in vivo.Here we develop copper sulfide doped hollow mesoporous organosilica nanoparticles(HMON@CuS)for carrying oxygen saturated PFP(O2-PFP@HMON@CuS-PEG)to tumor sites,overcoming hypoxia-associated RT resistance.The hyperthermia induced by laser irradiated CuS can activate PFP vaporization,and the released bubbles can serve as contrast enhancement agent of ultrasound(US)imaging,but also can trigger the release of oxygen.Cell experiments demonstrate significant enhancement of RT after supplying extra oxygen.After conjugating 64Cu,positron emission tomography(PET)can be used to monitor the in vivo distribution of theranostics.The theranostics have relatively long blood terminal half-life,and the accumulation in tumor reaches peak at 24 h after intravenous injection.Also CuS can provide photoacoustic(PA)imaging ability.Hopefully,the custom-designed oxygen-carrying nanotheranostics in this study will establish a versatile PET/US/PA imaging guided oxygen-sensitized radiotherapy.