Construction Of Metal/Dendrimer Based Hybrid Nanoplatforms For Enhanced Theranostics Of Tumors

Cancer is a leading cause of death worldwide,and theranostics have emerged in recent years to provide an efficient,personalized,and safer alternative in cancer management.Nanotheranostics are the noninvasive concept that accredits diagnostic imaging and the simultaneous in situ use of therapy,with the monitoring of therapy process.Presently,multi-step process during the manufacturing of these multifunctional theranostic agents has limited the biomedical application of nanotheranostics.It is urgent to search for novel nanotheranostics to efficiently integrate cancer diagnosis and treatment via sample and effective methods.Moreover,the efficacy of nanotheranostics is mainly determined by how much effective drugs and imaging contrast agent can be delivered to the solid tumors.The extravasation and penetration efficiencies are still inefficient because of the complexity of tumor microenvironment barriers and the tumor heterogeneity.Meanwhile,the efficient delivery of therapeutic and imaging agent into tumors is a major challenge for cancer theranostics.With the development of nanotheranostics,dendrimers represent a novel strategy in cancer treatment both as nanocarrier and as drug active per se.In this dissertation,we used the dendrimers（poly（amidoamine）dendrimer or phosphorous dendrimer）as the basis nanomaterial to design functional metal/dendrimer-based hybrid nanoplatforms for tumor theranostics.We first explored the dendrimer-based copper complexes for the T₁-weighted magnetic resonance（MR）imaging/chemotherapy of tumor.In particular,we used low dose radiotherapy（RT）and ultrasound technology to increase the enrichment of copper complexes in the tumor site to improve its diagnosis and treatment.Then,we further employed the hypoxia-targeted dendrimer-based Au/Gd nanohybrids for the dual-mode imaging guided sensitized RT.The main contents were detailed as follows:（1）Poly（amidoamine）dendrimer-coordinated copper（II）complexes as a theranostic nanoplatform for the RT-enhanced MR imaging and chemotherapyThe development of a powerful nanoplatform to realize the simultaneous diagnosis and therapy of cancer using a similar element for theranostics remains a critical challenge.Herein,a theranostic nanoplatform based on pyridine-functionalized generation 5 poly（amidoamine）dendrimers complexed with copper（II）（G5.NHAc-Pyr/Cu（II）complexes）was prepared for RT-enhanced MR imaging and the radio-chemotherapy of both tumors and tumor metastasis.In this study,amine-terminated G5 dendrimers were covalently linked with 2-pyridinecarboxylic acid,acetylated to neutralize their remaining terminal amines,and complexed with Cu（II）through both the internal tertiary amines and the surface pyridine groups to form the G5.NHAc-Pyr/Cu（II）complexes.The dendrimer-based copper complexes were able to inhibit the proliferation of different cell lines with half-maximal inhibitory concentrations ranging from 4 to 10μM and induce significant cancer cell apoptosis.Due to the presence of Cu（II）,the G5.NHAc-Pyr/Cu（II）complexes displayed an r₁relaxivity of 0.7024 m M^-1s^-1,enabling effective in vivo MR imaging of tumor xenografts and lung metastatic nodules.Further,under RT conditions,the tumor MR imaging sensitivity could be significantly enhanced,and the G5.NHAc-Pyr/Cu（II）complexes enabled the enhanced chemotherapy of both a xenografted tumor model and a blood-vessel metastasis model.（2）Promoting theranostics of copper（II）-conjugated phosphorus dendrimers via ultrasound targeted microbubble destruction technologyDesign of simple-component theranostic agents with enhanced tumor accumulation represents a novel strategy in the area of precision nanomedicine for effective tumor theranostics.Herein,an innovative theranostic strategy based on ultrasound-enhanced tumor accumulation of a theranostic agent of phosphorus dendrimer-copper（II）complexes（1G₃-Cu）was reported.The employed 1G₃-Cu complexes represented a drug-free nanotheranostic agent with a simple composition possessing an r₁ relaxivity of 0.7432 m M^-1s^-1 for T₁-weighted MR imaging and an IC₅₀ of 1.24μM to inhibit the growth of a pancreatic cancer cell line.The cancer cells could be inhibited by the 1G₃-Cu complexes through the activation of the apoptotic process with the upregulation of Bax,P53,and PTEN,downregulation of Bcl-2,and decrease of intracellular ATP.With the assistance of ultrasound targeted microbubble destruction（UTMD）technology that can increase cell membrane permeability temporarily via sonoporation effect,the 1G₃-Cu complexes enabled enhanced tumor MR imaging and chemotherapy due to their improved tumor accumulation.With the proven minimal toxicity to normal tissues at imaging and therapeutic doses,the prepared 1G₃-Cu complexes may be potentially employed for UTMD-enhanced theranostics of different types of cancer.（3）Targeted tumor hypoxia dual-mode imaging and enhanced radiation therapy using dendrimer-based nanosensitizersThe efficacy of RT is often limited by the poor response of hypoxia inside most of solid tumors.Development of a theranostic nanoplatform for precision imaging-guided sensitized RT of tumor hypoxia is still challenging.The creation of hypoxia-targeted dendrimer-entrapped gold nanoparticles complexed with gadolinium（III）（Gd-Au DENPs-Nit）was developed for dual-mode CT/MR imaging and sensitized RT of hypoxic tumors.In this work,poly（amidoamine）dendrimers G5 were partially conjugated with Gd（III）chelator,entrapped with Au nanoparticles,and conjugated with hypoxia-targeting agent nitroimidazole via a polyethylene glycol linker,and ended with chelation of Gd（III）and conversion of their leftover amine termini to acetamides.The designed dendrimer-based nanohybrids having 3.2-nm Au cores exhibited an excellent X-ray attenuation effect,acceptable r₁ relaxivity(1.32 m M^-1s^-1),and enhanced cellular uptake in hypoxic cancer cells,affording efficient dual-mode CT/MR imaging of tumor hypoxia.Under X-ray irradiation,the Gd-Au DENPs-Nit nanohybrids could produce reactive oxygen species,promote DNA damage and prevent DNA repair,facilitating sensitized RT of hypoxic cancer cells in vitro and tumor hypoxia in vivo.The developed hypoxia-targeted dendrimer-based nanohybrids may be employed as both contrast agents and nanosensitizers for precision tumor hypoxia imaging and sensitized tumor RT.