Construction Of Multifunctional Dual-drug Delivery Systems For Hepatocellular Carcinoma Theranostics

Nanomedicine has been widely used in the treatment of cancer with the development of nanotechnology.Multifunctional nanoparticles?NPs?as dual-drug delivery systems can significantly reduce the drug toxicity and dosage,effectively overcome the resistance of cancer cells and achieve the synergistic cancer therapy.Furthermore,the multi-mode imaging?such as computed tomography?CT?,magnetic resonance?MR?and upconversion luminescence?UCL??is competent for providing comprehensive and valuable information for evaluating and adjusting the treatment,which greatly favors the personalized therapy for an individual patient and enhances synergistic theranostics.This paper designed the several multifunctional dual-drug delivery systems and explored its potential applications including drug delivery,stimulus response release,photothermal ablation of tumor cells,multi-mode imaging,inhibition of the metastases and so on.The specific research content and results are as follows:?1?Here,we firstly reported Yin Yang-like ultrasmall NPs-stacked oleic acid-NaYF₄:Yb,Er@hollow porous SiO₂?Yin Yang-like OA-UCNPs@HPS?NPs with a hydrophobic eccentric hollow structure and hydrophilic exterior surface via a novel method.The obtained NPs achieved the loading of multiple hydrophobic/hydrophilic guests into the discrete rooms and the release of each one from the independent channels to reduce the undesirable adverse effects of different guests.We chose the hydrophobic hydroxycamptothecin?HCPT?and hydrophilic doxorubicin?DOX?as drug models for exporing the inhition efficiency of the tumor.The in vitro and in vivo?cell line-derived xenograft?CDX?and patient-derived xenograft?PDX?models?results demonstrated that the HCPT/DOX-loaded NPs could act as excellent theranostics agents for multimodal imaging-guided synergic dual-drug cancer therapy of hepatocellular carcinoma?HCC?.?2?The synthesized oleic acid-NaYF₄:Yb,Er/polydopamine?OA-UCNPs/PDA?double-layered nanobowls with unique nanostructure have been successfully engineered with hydrophilic anti-cancer drug DOX/hydrophobic anti-angiogenic drug sorafenib?SF?,which can serve as dual-drug delivery system for site-specific pH/NIR dual-stimuli drug release.Then we established an aggressive whole-body spreading orthotopic tumour model closing to actual cases of human patients,the disseminated tumour cells could theoretically be ideal natural carriers for drug-loaded double-layered nanobowls to target individual cancerous cell of metastases,which was used to evaluate the anti-metastases effect of double-layered nanobowls.The results indicated the group of DOX/SF-loaded double-layered nanobowls effectively suppressed primary tumor growth and metastases.Furthermore,the multi-mode UCL/MR/CT imaging is competent for providing comprehensive and valuable information for evaluating and adjusting the treatment.The employ of cancer cell-mediated anti-metastasis therapeutic strategy delivering drugs into metastatic cells to defeat tumor metastases provides directions in the fields of anti-metastasis therapy.?3?In order to effectively eliminate tumors in deep tissue by NPs-based drug delivery system.First,we synthesized the OA-UCNPs/PDA nanobowls,whereafter,the Au nanoflowers were attached on the outside of the PDA bowl by the selective growth strategy,resulting the OA-UCNPs/PDA-Au nanoflower Janus NPs?OA-UCNPs/PDA-AuF JNPs?.The extensive absorption of the OA-UCNPs/PDA-AuF JNPs in the NIR-II window was demonstrated in the UV-vis-NIR spectrum,which indicated the superior photothermal effects of OA-UCNPs/PDA-AuF JNPs in the NIR-II window.The obtained OA-UCNPs/PDA-AuF JNPs were programmed to integrate the independent storage spaces for loading of HCPT/DOX with controllable proportion,ideal photothermal conversion efficiency,pH/NIR bimodal-triggered controlled drug release properties and multi-mode imaging ability into one single JNP,which could act as the promising theranostic nanoagents for multimodal imaging-guided synergic dual-drug chemo-photothermal therapy of HCC.The group of HCPT/DOX-loaded JNPs under a 1064 nm laser exhibited the highest tumor inhibition efficiency in the CDX and PDX models.