Peptide Regulated Self-assembly Of Photosensitive Molecules And Tumor Phototheranostic Applications

Photodiagnosis and phototherapy show advantages of safety and noninvasiveness,which are of utmost importance for tumor therapy.Photosensitive molecules are key elements in phototheranostic systems.Fabrication of nanodrugs based on supramolecular chemistry have emerged as a novel strategy to improve photosensitive molecules bioavailability and therapeutic efficacy.Designing building blocks and regulating self-assembly of photosensitive molecules by manipulating noncovalent interactions to elucidate the potential relationship between structure and function of nanodrugs,thereby to achieve precise and multifunctional phototheranostics is challenging.Oligopeptides with customized structures were selected as building blocks to co-assembly with photosensitive molecules.Synergistic noncovalent interactions promoted the formation of peptide-based nanodrugs,and realized the control or optimization of photophysical/photochemical pathways of photosensitive molecules,which enhanced efficiency and flexibility of tumor phototheranostics.Furthermore,introducing bioactive oligopeptides as self-assembly motifs amplified the combinational treatment outcomes,and promoted their clinical applications.The dissertation mainly included the following contents:1.Oligopeptides regulated co-assembly of near-infrared cyanine molecules via noncovalent interactions,obtaining two-photon absorption(TPA)nanoprobes.The nanoprobes showed unique photo-oxidation enhanced photoluminescence and can be applied for in vivo imaging with high-resolution.Driven by hydrophobic interactions and ?-? stacks,oligopeptides and cyanine molecules co-assembled into nanoprobes.Regulation on stacks of cyanine molecules at the nanoscale promoted their singlet oxygen-mediated dimers formation during photo-irradiation process,which increased electron delocalization and thereby enhanced two-photon nonlinear absorption.The nanoprobes showed unique properties including photo-oxidation enhanced photoluminescence,excellent colloidal-and physiological stability.Significantly,cyanine-based nanoprobes showed larger TPA cross section and better imaging signal-to-noise ratio than traditional TP A dye rhodamine B.Hence,the processes of nanoprobes enrichment,accumulation within blood vessels in real time were monitored and high-resolution imaging application at the single-cell level in vivo was realized.2.Manipulating hydrophobic interactions achieved flexible structure switch of phthalocyanine-peptide(PF)conjugates from "aggregates" to "monomer",and integrated their multi-model theranostic functions.The designed amphiphilic PF conjugates can self-assemble into nanoparticles.Supramolecular photothermal effect endowed the nanoparticles with excellent photothermal conversion performance,enabling their photoacoustic imaging-guided photothermal therapy.Intriguingly,competitive hydrophobic domains in phospholipid bilayer of cell membranes promoted dis-assembly of nanoparticles,which restored PF molecules capability of fluorescence imaging-guided photodynamic therapy.Coupling dual model imaging modalities realized the visualization of switchable photoactivities,which indicated optimal therapeutic window.Combining photothermal and photodynamic therapy enhanced anti-tumor therapeutic efficacy.3.Clinical approved and immuno-active thymopentin was chosen as the building block to regulate self-assembly of indocyanine green for constructing nanofibrils.The therapies of photothermal ablation and immunomodulation of nanofibrils were combined for pancreatic cancer treatment.Driven by directional hydrogen bonding interactions,water-soluble binary building blocks co-assembled into nanofibers with high aspect ratios.Supramolecular nanostructures promoted the long-range ordered arrangement of indocyanine green molecules,therefore enhanced photophysical and photochemical performance,colloidal-and physiological stability of nanofibrils.Significantly,thymopentin promoted the proliferation and differentiation of antitumor immune cells.After photothermal ablation on primary tumor,long-term and moderate immunomodulation inhibited tumor growth,metastasis and recurrence.In summary,supramolecular nanodrugs were fabricated by co-assembly strategy of oligopeptides and photosensitive molecules in harnessing of multiple and synergistic noncovalent interactions.The obtained nanodrugs optimized photophysical and photochemical properties of photosensitive molecules,enhanced the stabilities of functional components,and therefore realized effective,precise and multifunctional phototheranostic applications.