Heavy-Atoms Modulated Self-Assembled BODIPY Photosensitizers For Tumor Phototherapy

With the wide applications of nanomaterials and technologies in the fields of drug delivery,disease diagnosis and treatment,nanomedicine has been established and rapidly developed.The outstanding features of nanomaterials pave a way to overcome the shortcomings in the research field of conventional medicine,such as size effect,quantum effect,large specific surface area and so on.Nanodrugs or nanocarriers have many advantages,such as high drug loading rate,long-term blood circulation time,excellent tumor targeting,and relatively low drug toxicity.Up to now,many nanomedicines or drug candidates have been applied or tested in the clinical or preclinical testing stages,such as polymeric micelles-,liposomes-,and protein-chemodrugs complexes.In addition,nanodrugs for emerging therapeuticcal phototherapy became a promising research field of precision tumor treatment.Phototherapy was considered as a novel cancer treatment method,owing to high treatment accuracy,high safety,high selectivity and less side effect.Phototherapy can be divided into photodynamic therapy(PDT)and photothermal therapy(PTT)according to the photophysical process,in which the photosensitizer in the tumor site was excited by light and subsequently converted the absorbed energy into hyperthermia or reactive oxygen species(ROS)to kill tumor cells via photochemical reactions or photophysical reactions.However,many shortcomings of conventional photosensitive drugs hampered their further clinical use,such as poor photostability,shallow depth of treatment,and poor therapeutic efficacy.Herein,fluoroborine dipyrrole-based dyes(BODIPY)were designed and synthesized with different iodine numbers and substituted positions through chemical synthesis methods.The aim was to increase the intersystem crossing rate of BODIPY cores and promote non-radiative transition probabilities by heavy atom effect,resulting in enhanced photodynamic and photothermal activities.In addition,BODIPY nanophotosensitizers was further linked with polyethylene glycol(PEG)chains in order to self-assemble into nanoparticles for tumor phototherapy.Finally their photodynamic and photothermal activities at the cellular and animal level was investigated in details in photodynamic/photothermal synergistic therapy.Chapter 1: Introduction on research background.In this chapter,we summarized and discussed the current situations and the latest advances of nanomedicine in tumor therapy,in particular tumor phototherapy.In the part of tumor phototherapy we described the BODIPY-based dyes in the development of novel photosensitizers.In light of this background,we proposed our research work on the design of BODIPY-based photosensitizers for tumor synergistic phototherapy.Chapter 2: Syntheses and characterizations of BODIPY-based photosensitizer and their nanoparticles.A series of BODIPY-based photosensitizers with different numbers of iodine atoms were synthesized by multi-step method.Their corresponding nanoparticles was further fabricated,namely BMs,2-IBMs,4-IBMs and 8-IBMs nanomicelles.The photophysical properties of BMs,2-IBMs,4-IBMs,8-IBMs nanomicelles and their controls were investigated in details.We found that the modification of the iodine atom s significantly can promote intersystem crossing and non-radiative transitions,in which 4-IBMs shows outstanding photophysical activities.Chapter 3: Biological evaluation of BODIPY-based photosensitizers and their nanoparticles at the cellular level.The biological activities of 2-IBMs,4-IBMs and 8-IBMs nanomicelles in tumor cells was explored,involving cellular uptake of by tumor cells,subcellular localization,and lysosomal membrane rupture by light-induced ROS.The biological effects,the toxicity and cell death mechanism on 4T1 tumor cells were investigated as well.The experimental results indicate that 4-IBMs exhibits excellent phototoxicities to tumor cell.Chapter 4: Biological evaluation of BODIPY-based photosensitizers and their nanoparticles at the animal level.The in vitro biological activities of 2-IBMs,4-IBMs and 8-IBMs nanomicelles were investigated,including bio-distribution and tumor inhibition effects.Moreover,H&E experiments were undertaken to evaluate their biosafety.The experimental results indicate that 4-IBMs exhibits excellent tumor bio-accumulation and photo-induced antitumor effects.