Investigation On CuInS₂/ZnS Quantum Dots Based Tumor Targeted Theranostics System

Cancer has gradually become a major cause of death worldwide.It is of great important significance that achievement of early diagnosis and treatment of cancer.Fluorescence imaging is a growing field for early diagnosis because of great imaging speed,high sensitivity,non-radioactive hazard.Nevertheless,fluorescence imaging has relatively low spatial resolution and unavailable in deep tissue in vivo.Recently,the combination of multimodal imaging and therapeutic agents to be a multifunctional platform becomes a main research direction of biomedical materials with the development of nanotechnology.Due to the deeper tissue penetration,high near-infrared（NIR）photoluminescence,great stability,NIR quantum dots（QDs）have been commonly used as fluorescence probe for imaging.However,the potential toxicity of heavy metal elements has always limited the clinical application of NIR QDs.The development of multifunctional QDs based contrast agent with good biocompatibility,high fluorescent quality and great colloidal stability,can play an important role in early diagnosis and treatment of tumor.Heavy-metal free hydrophobic CuInS₂/Zn S（ZCIS）QDs with NIR photoluminescence were synthesized to avoid the potential toxicity of heavy metal element.In order to improve the targeting ability of ZCIS QDs to tumor cells,hyaluronic acid was modified on the surface of bovine serum albumin（BSA）coated ZCIS QDs.Cellular experiments showed that the cellular nonspecific uptake ability could be reduced through BSA coating.Furthermore,HA modified BQDs were able to be taken up by He La cells through the CD44 mediated receptor-ligand interaction,and the cellular uptake ability of higher molecular weight HA modified BQDs was significantly better than that of lower molecular weight HA.To overcome the shortcomings of NIR fluorescence imaing,a multifunctional nanotheranostic agent was developed by conjugating both HA and BQDs onto the surface of magnetic Prussian blue nanoparticles.The obtained nanoagent could serve as an efficient contrast agent to simultaneously enhance NIR fluorescence and T2 weighted magnetic resonance imaging greatly.The coexistence of magnetic core and CD44 ligand hyaluronic acid was found to largely improve the specific uptake of the nanoagent by CD44 overexpressed He La cells upon applying an external magnetic field.After intravenous injection of the nanoagent and treatment of external magnetic field,the tumor in nude mice was efficiently ablated upon NIR laser irradiation and the tumor growth inhibition was more than 89.95%.In order to improve the effect of multimodal imaging,gadolinium chelated ZCIS QDs were prepared through surface ligand exchange and modification.The hydrodynamic diameter of QDs@DTDTPA-Gd was about 24.2 nm.Both in vitro and in vivo experiments proved that the multifunctional QDs could use for NIR fluorescence imaging and T1 weighted magnetic resonance imaging.Besides,the r1 relaxation rate of QDs@DTDTPA-Gd was 9.91 m M-1s-1,which was two times higher than that of clinical approved DTPA-Gd.Photothermal therapy of tumor were easy to recur,to overcome this problem,a non-viral vector with the function of in vivo real time imaging was developed.A multifunctional contrast agent was fabricated by p EGFP-C1 plasmid DNA complexed ZCIS QDs onto the surface of ST68 microbubbles（MBs）,to achieve efficient delivery of gene drug under the guidance of NIR fluorescent and ultrasonic bimodal imaging.The diameter of obtained QDs@PEI/pDNA@MBs 2.52±2.10 μm,which was meet the size requirement of medical ultrasound contrast agent.Cellular experiments showed that p EGFP-C1 complexed QDs could be released and achieve efficient gene transfection with He La cells through ultrasound-targeted microbubble destruction of multifunctional contrast agent.In brief,a series of heavy-metal free NIR ZCIS QDs based multifunctional agent were developed for diagnosis and treatment of cancer.Our research further expanded improvement function of ZCIS QDs in cancer diagnosis and treatment.The study has some certain significance to the development of multifunctional theranostic agent for clinic.