| Self?assembled small molecules based drugs or prodrugs,fluorescent probes,and smart multifunctional fluorescent drug delivery systems have crucial importance in drug discovery,biological research and clinical practices.These small molecules have excellent biocompatibility,structural simplicity and chemical versatility which make them suitable candidate for widespread applications.Although there is diverse progress in this field,still there is need to design assorted and novel small molecules to fulfill clinical and research applications.My Ph.D dissertation is one step toward the development of novel small molecules for drug release,imaging and recognition.In this research effort,we designed self-assembled small molecules,which are expected to be used for the early diagnosis of cancer and activatable small molecular probes for highly sensitive analysis of biologically relevant important molecules(e.g.metal ions,anions,enzymes).In second chapter of this dissertation an anticancer prodrug based on hydrogelator precursor is designed.Cancer is main cause of death globally.In chemotherapy,etoposide is used as tumor targeting drug but this drug has some adverse effects on human body.In this project the efficiency of etoposide is improved with help of hydrogelator precursor.In vitro studies were performed with help of HeLa cells and result echoed improved efficiency of etoposide.Meanwhile,same cells were injected into mice for in vivo analysis and we observed that the designed drug show slow release and remains at tumor site for long time.These exceptional outcomes echoed that this is a progress to improve the therapeutic effects of anticancer drugs in the future.In chapter 3 of this dissertation,we reported that wilson's disease(WD),which might lead to acute liver failure,is an inherited disorder characterized with an excess accumulation of Cu2+ in brain,liver,and other vital organs.In clinic,decreased serum alkaline phosphatase(ALP)concentration is used for WD diagnosis.But according to our knowledge,using a fluorescent probe to simultaneously detect multiple factors in WD(e.g.,Cu2+,pyrophosphate(PPi),and ALP)haven't published.Herein,we rationally designed a fluorescent switch(E)-8-((4 methylbenzylidene)amino)napthalen-1-amine(L)and applied for selective detections of Cu2+,PPi,and ALP in vitro and in living cells with "Off","On",and "Off' fluorescence signals,respectively.Considering the obvious correlations among Cu2+,PPi,and ALP in WD,we hope that our fluorescent probe L could probvide a theoretical basis for the early diagnosis of WD by fluorescence probe in vitro.In chapter 4 of this dissertation,we found that targeted delivery of chemotherapies to the tumor cells is one of the biggest challenges in cancer treatment.Herein,we synthesized smart dipeptide nanoparticles for cancer specific targeting and intracellular pH sensitive release of chemotherapies.Diphenylalanine peptide was synthesized and further developed as nanoparticles(NPs)which were functionalized with folic acid utilizing carbodiimide reaction.Doxorubicin(Dox)was loaded to self-assembling nanoparticles of both non-functionalized(FF-Dox)and folate functionalized peptides NPs(FA-FF-Dox).The in vitro experiments in HeLa cells revealed that the FA-FF-Dox formulation yielded significantly higher endocytosis and greater cytotoxicity.Moreover,the experiments also revealed the pH sensitive release of Dox for both FA-FF-Dox and FF-Dox due to the protonation of Schiff base and amines present in peptides at low pH,enhancing intracellular release subsequent to receptor mediated endocytosis.The in vivo biodistribution study revealed significant greater accumulation of Dox in tumors 24 h after intravenous administration of FA-FF-Dox to the tumor bearing mice,in comparison with FF-Dox and free Dox.Our research offered a new paradigm for enhanced endocytosis and pH sensitive release of anticancer therapies by using self-assembled,drug laden and functionalized dipeptide nanoparticles. |
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