Functional Dipeptide Derivatives:Molecular Design,Self-assembly And Antitumor Phototherapy

Cancer has been become the global threat to human beings,necessary to utilize nanotechnology for the treatment of this fatal disease.Therefore,light based modalities like photothermal and photodynamic therapies are increasingly attractive by using appropriate photosensitive agents,either through a drug carrier or direct through suitable fabrication of nanostructures.Due to the fundamental limitation of photosensitizers or drug carriers,biological inherent functional dipeptide derivatives were used for the improvement of phototherapies.Photothermal agents are potent agents to harvest light energy and convert it into heat,offering a targeted and remote-controlled way to destroy carcinomatous cells and tissues.Inspired by the biological organization of polypeptides and porphyrins in living systems,therefore,we have developed a supramolecular strategy to fabricate photothermal nanodots through peptide-modulated self-assembly of photoactive porphyrins.The self-assembling nature of porphyrins induces the formation of J-aggregates as substructures of the nanodots,and thus enables the fabrication of nanodots with totally inhibited fluorescence emission and singlet oxygen production,leading to a high light-to-heat conversion efficiency of the nanodots.The peptide moieties not only provide aqueous stability for the nanodots through hydrophilic interactions,but also provide a spatial barrier between porphyrin groups to inhibit the further growth of nanodots through the strong ?-stacking interactions.Thermographic imaging reveals that the conversion of light to heat based on the nanodots is efficient in vitro and in vivo,enabling the nanodots to be applied for photothermal acoustic imaging and antitumor therapy.Antitumor therapy results show that these nanodots are highly biocompatible photothermal agents for tumor ablation,demonstrating the feasibility of using bioinspired nanostructures of self-assembling biomaterials for biomedical photoactive applications.The hydrophobic drugs are suffering from many issues for delivery to the locality of tumor.Therefore,the stimuli responsive nanosystems are highly appreciated especially short-peptide based responsive carriers.Here we developed the diphenlyalanine conjugate(DFF)to form the nanofibers.DFF is self-assembled with Ce6 drug,through non-covalent interactions like hydrogen bonding,hydrophobic interaction,and ?-? interaction,to fabricate the nanofibers.These nanofibers are amyloidal fibrils with beta sheet secondary structures.The short fibrils have the redox responsiveness due to the presence of disulfide bond.Furthermore,cellular uptake of photosensitizer is enhanced as compared to free Ce6.In vitro photodynamic therapy revealed that the photocytotoxicity is improved 2.5 fold according to the IC50 value relevant to free Ce6.The in vivo biodistribution demonstrates the efficient accumulation of nanofibers to tumor,there was significant inhibition in the tumor size.Supramolecular self-assembly of functional dipeptides to form hydrogel is a key motive for drug carrier in the field of antitumor therapy.Therefore,we design a low molecular hydrogelator based on diphenylalanine,linked with long hydrocarbon chain including disulfide bond in the center of molecule,deprotonation of carboxylic acid groups at terminus form the negatively charged viscous liquid.The addition of positively charged polylysine(PLL)is enabling to form the injectable nanofibrous hydrogel.The electrostatic,hydrophobic interaction and intennolecular hydrogen bonding are the driving forces for co-assembly of supramolecular hydrogel.Moreover,the stability of hydrogel is decisive property for injectability in the drug delivery;hence,PLL is responsible for mechanical stability.The nanofibrous hydrogel is a potent candidate for the controlled release of photodynamic drug to the locality of tumor;the drug is released in a sustained way by reduction of disulphide bond due to inheritable GSH in the tumor.The in vivo biodistribution of hydrogel exhibiting hydrophobic drug Ce6 reveal that the drug was released from hydrogel in a sustained way.In addition,the tumor in the treatment group was eradicated after three time laser exposure as compared to groups,which were irradiated one and two times.There was also inhibition observed in other two groups which were irradiated one and two times as compared to control.These results support the idea of one injection multiple treatment phenomenon.