Soft Nanomaterials For Innovative Cancer Imaging And Therapy

Cancer has become one of the major diseases to threat human health.Commonly used cancer therapeutics including surgery,chemotherapy,and radiotherapy,have many limitations such as toxic side effects and limited therapeutic efficacy.Therefore,developing novel cancer therapies and combining different single treatment are usually considered as the promising strategies to improve therapeutic efficiency.The development of nanotechnology and the combination with medicine provide new opportunities for tumor diagnosis and treatment.Nanomedicine is the medical application of nanotechnology,which ranges from the medical applications of nanomaterials and biological devices,to nanoelectronic biosensors,and even possible future applications of molecular nanotechnology such as biological machines.In the past decade,numerous types of inorganic nanomaterials have shown high efficacy for cancer therapy in animal experiments.However,the non-biodegradable nature of most of these inorganic nanoparticles have significantly hampered their clinical applications owning to their potential long-term toxicity.Albumin,the major component of serum proteins,is a promising nano-carrier owning their natural structural roles,easy and cost effective biological production,functional tunability by genetic engineering,and full biocompatibility.In this dissertation,we summarized the application of albumin-based multifunctional nanoparticles for tumor detection,multimodal imaging,novel cancer therapies,and demonstrated the unique properties and advantages of albumin nanoparticles in biological applications.In addition,we also explored the application of combined photothermal and immunotherapy,which may be able to eliminate primary tumors,attack and kill spreading metastatic tumors,and finally offer immune-memory protection to prevent tumor relapse.The main results are summarized as follows:Chapter 1:This chapter summarizes the recent research progresses of albumin-based nanomaterials for biomedical applications and the motivations of the research in this dissertation.Chapter 2:Near-infrared dye bound albumin for imaging-guided photothermal therapy.The synthesized near-infrared dye,IR825,is bound with HSA,forming a HSA-IR825 complex with unique optical behavior,which enables imaging and photothermal therapy at separated wavelengths both with optimized performances.HSA-IR825 appears to be a powerful photothermal agent not only to effectively ablate subcutaneous tumors upon intravenous injection,but more remarkably,also to inhibit tumor metastasis after surgery by burning the sentinel lymph nodes with metastatic tumor cells.Chapter 3:’Abraxane-like’ nano-drug for combination cancer therapy to treat subcutaneous and metastatic breast tumors.The multifunctional ’Abraxane-like’ nano-drug is formulated by simply mixing three FDA-approved agents,HSA,PTX,and ICG together,which exhibits great performances in both imaging,chemotherapy and photothermal therapy.Utilizing our newly formulated HSA-ICG-PTX nano-drug,highly effectively combined photothermal&chemo-therapy under the guidance of NIR imaging is conducted.Chapter 4:Drug-induced self-assembly of modified albumins as nano-theranostics for tumor-targeted combination therapy.HSA pre-modified with either a photosensitizing molecule,or a tumor-targeting peptide,would self-assemble in the presence of a hydrophobic anti-cancer drug PTX,to form tumor-targeting nanoparticles with multiple imaging and therapy functionalities.Chapter 5:Albumin-MnO2 nanoparticles as pH-/H2O2-responsive dissociable nano-carriers to modulate tumor hypoxia for effective combination therapy.HSA pre-modified with either a photosensitizer,or pro-drug of cis-platinum,as the template to form MnO2 nanoclusters through biomineralization.This work presents an interesting concept of nanoscale drug delivery system which not only shows TME responsive size changes for enhanced intra-tumoral diffusion,but also is able to modulate the unfavorable TME to create better conditions for improved cancer therapy.Chapter 6:A self-assembled albumin-based nanoprobe for in vivo ratiometric photoacoustic pH Imaging.A pH sensitive nano agent self-assembled from human serum albumin and two types of dye molecules:one is a pH-inert dye IR825,the other is a pH-responsive BOPx dye is developed for in vivo ratiometric photoacoustic pH imaging.Utilizing such newly formulated nano agent,the tumor pH as well as the instant pH change in the tumor microenvironment could be accurately detected by photoacoustic imaging.Chapter 7:Albumin-NIR dye self-assembled nanoparticles for photoacoustic pH imaging and pH-responsive photothermal therapy for large tumors.A pH-responsive NIR dye Croc is able to induce the self-assembly of HSA to form HSA-Croc nanoparticles useful not only for real-time ratiometric photoacoustic pH imaging,but also for pH responsive photothermal therapy with excellent therapeutic results on large tumors.Chapter 8:H2O2-responsive liposomal nanoprobe for photoacoustic inflammation imaging and tumor theranostics.HRP and its substrate ABTS are simultaneously loaded into liposome,forming Lipo@HRP&ABTS nanoprobe for in vivo H2O2 detection with great specificity and sensitivity.It is useful not only for in vivo inflammations or tumors detection,but also for tumor-selective photothermal therapy with high efficacy.Chapter 9:Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy.ICG(a photothermal agent),and R837(a Toll-like-receptor-7 agonist),are co-encapsulated by PLGA,forming PLGA-ICG-R837 nanoparticles.Utilizing photothermal effect of PLGA-ICG-R837 to eliminate primary tumors,generating tumor-associated antigens,which in combination with the anti-CTLA4,generating immunological responses,which is able to inhibit cancer metastases,and prevent tumor relapses.In summary,this thesis illustrates the applications of albumin-based nanoparticles in tumor detection,multimodal imaging guided cancer therapy.Our results greatly promise application of those biocompatible albumin nanomaterials in biomedicine in the future.