Organic Nanomaterials For Phototherapy Of Cancer

Cancer is one of the greatest threatens to human health around the world.Tough tremendous efforts have been devoted to find out the development mechanisms of cancer,only limited successes have been achieved in the development of novel cancer therapeutics for effective cancer treatment in the past several decades.Therefore,to satisfy the growing amounts of cancer incidence and mortality,developing novel cancer therapeutics with improved safety,specificity and efficacy has become a multidisciplinary research hotspot.For instance,caner phototherapy,including photothermal therapy(PTT)and photodynamic therapy(PDT),has recently attracted plenty of research attentions for efficient cancer treatment owing to its high selectivity,improved safety and enhanced therapeutic efficacy compared to those conventional cancer therapeutics.In this doctoral dissertation,we focused our research interests in the fabrication of novel multifunctional organic nanomaterials for efficient phototherapy of cancer.With near infrared(NIR)absorbing nanoagents like polypyrrole(PPy)and IR825 based J-aggregates as the photothermal agents,we have rationally designed several different nanotheranostics forimaging guided PTT or combined cancer therapy,leading to efficient cancer treatment with improved selectivity and safety.Moreover,it has been uncovered that efficient tumor hypoxia relief could efficiently sensitize both PDT and radiotherapy in which oxygen is involved in the process of cancer cell killing,thus contributing to excellent synergistic cancer treatment outcomes.This doctoral dissertation presents the fabrication of several different organic nano-theranostics,aiming at developing innovative strategies for efficient phototherapy of cancer with improved efficacy,selectivity as well as safety.The main contents and conclusions are summarized as follows:1.In the first study,we successfully synthesized polypyrrole encapsulated ultra-small iron oxide nanoparticles(IONP@PPy)via the in situ polymerization method,which was then modified through a noncovalent layer-by-layer(LBL)assembly and further covalent conjugation of branched polyethylene glycol(PEG),obtaining physiologically stable IONP@PPy-PEG nanocomposites.By utilizing the excellent NIR absorbance of PPy for efficient photoacoustic(PA)imaging and photothermal conversion as well as the T2-weighted magnetic resonance(MR)contrast ability of IONPs,such IONP@PPy-PEG was demonstrated to be a promising multifunctional nanoplatform for imaging guided photothermal therapy of cancer.2.To further improve the biocompatibility and feasibility for surface functionalization of those PPy based nanocomposites,we utilized chlorin e6(Ce6)conjugated bovine serum albumin(BSA)as the stabilizer in the polymerization of PPy,obtaining multifunctional PPy@BSA-Ce6 nanocomposites via a simple one-step approach.Without needing any additional surface functionalization,the obtained PPy@BSA-Ce6 showed excellent physiological stability and promising capacities for both photothermal and photodynamic therapy.As evidenced by both in vitro and animal experiments,we uncovered that the combination therapy of PTT and PDT would contribute to remarkably enhanced therapeutic efficacy compared to those bare PTT or PDT under the same treatment conditions,demonstrating to be a promising strategy for effective cancer therapy.3.In this study,we successfully prepared a unique type of J-aggregates of IR825,a NIR molecule with excellent photostability and photothermal conversion ability,in the presence of a cationic polymer polyallylamine hydrochloride(PAH).The formed nanoparticles were then loaded with negatively charged ultrasmall IONPs,obtaining multifunctional IR825@PAH-IONP-PEG nanocomposite.Compared to bare IR825 molecules,which show a broad NIR absorbance peak at 825 nm,such IR825@PAH-IONP-PEG showed an obviously red-shifted,narrowed while enhanced NIR absorbance with a peak at 915 nm.Moreover,owing to the superior tissue penetration depth and low non-specific tissue heating effect of 915 nm light in comparison with 808 nm and 980 nm light,such IR825@PAH-IONP-PEG after being irradiated with 915 nm laser showed an excellent photothermal treatment outcome under the guidance of MR imaging.4.As a follow-up study,we found that aforementioned J-aggregates formed by IR825 could also be utilized for efficient loading of doxorubicin(DOX),a model anti cancer drug.It was interestingly uncovered that the mild photothermal effect generated from the J-aggregates of IR825 irradiated with 915 nm laser at a low power density could significant promote the celluar internalization of DOX,thereby contributing to remarkably improved therapeutic effects compared with bare PTT and chemotherapy under the same therapeutic doses.This study indicates that combined photothermal&chemo-therapy is an efficient strategy for cancer treatment.5.Metformin(Met),a widely used oral hypoglycemic agent for the treatment of type II diabetes,has been recently reported to reduce the oxygen consumption of cancer cells by impairing the function of mitochondrial complex I,thus leading to improved responsiveness of cancer to both radiotherapy and chemotherapy.Motivated by this intriguing property,we intended to explore the influence of Met on the therapeutic efficacy of PDT by utilizing the biocompatible liposome as the drug carrier to simultaneously load both Met and hydrophobic Ce6(HCe6).Upon intravenous injection,as-prepared Met-HCe6-Liposome could efficiently relieve the tumor hypoxia as revealed by both ex vivo immunofluorescence staining and in vivo PA imaging,thus leading to remarkably improved PDT of cancer.This study indicates that it is a robust strategy to improve the treatment outcome of PDT via overcoming tumor hypoxia.6.In addition to applying the above mentioned strategy to relieve tumor hypoxia,oxygen shuttles such as perfluorocarbon(PFC),a well studied artificial blood substitute,has also been utilized to reoxygenate hypoxic tumors via directly deliver oxygen into tumors.In this study,we prepared nanodroplets of PFC with human serum albumin(HSA)as the stabilizer according to previous developed methods.It was found that such PFCnanodroplets showed great oxygen dissolving capacity and exhibited a burst-like oxygen release profile under the treatment of a low frequency ultrasonication(US).Via the blood circulation system,PFC nanodroplets with high oxygen loading after passing the lung would circulate into the tumor,in which oxygen is efficiently released from nano-PFC under US stimulation,resulting in dramatically enhanced tumor oxygenation as confirmed by both ex vivo immunofluorescence staining and in vivo PA imaging,thus leading to enhanced photodynamic therapy and radiotherapy.In this doctoral dissertation,we have systemically studied the fabrication of multifunctional organic nanotheranostics and their potentials for innovative phototherapy of cancer.It was found that the imaging guided PTT realized by rationally combining the imaging technique with PTT could significantly improve its therapeutic efficacy and selectively,as well as reduce its side effects to normal tissues.Besides,we uncovered that combination therapy of PTT with PDT or chemotherapy could contribute to synergistically improved treatment outcomes when compared with those mono-therapies.Moreover,it was intriguingly found that the tumor hypoxia relief could efficiently overcome the intrinsic resistance to PDT and radiotherapy with oxygen involved in inducing cell death,thus leading to excellent synergistic effect on inhibiting tumor growth.This doctoral dissertation presents a promising approach for the development of novel cancer therapeutic strategies,as well as some informative references for the construction of multifunctional nanotheranostics and their application for efficient cancer treatment.