Biological Function Of Several Kinds Of Drug And Drug Carrier

The traditional drug or drug delivery lacks of selectivity and targeting, which cause great toxic effect to normal tissue organ and bring pain to patients. Recently, study of drug targeting or drug carrier has become a research hotspot. Improving drug efficacy and decreasing drug toxicity are main goals of drug research. We focused on this field and made achievements in two aspects.(1) For the difficulties of treatment brain disease, we selected a potential peptide with the ability to transport into the brain via the nasal passage by using phage display.(2) To overcome poor effects and toxicity of antitumor drugs, we found cysteamine could enhance the chemotherapeutic effect of doxorubicin through autophagy modulation. Subsequently, I will summarize the main achievements we have made in the work.Part I: To select potential peptides with the ability to transport into the brain via the nasal passage, we applied a C7C phage peptide display library (Ph.D.-C7C) intra-nasally to anethesized rats and recovered phage from the brain tissue 45 minutes after phage administration. After three rounds of panning, 10 positive phage clones were selected and sequenced. Clone7, which exhibited highest translocation efficiency, was chosen for further studies. After nasal administration, Clone7 entered the brain within 30 minutes and exhibited translocation efficiency about fifty fold higher than a random phage. A 11-amino acid synthetic peptide derived from the displayed sequence of Clone7 (ACTTPHAWLCG) efficiently inhibited the nasal-brain translocation of Clone7. Both phage recovery results and fluorescent microscopy images revealed the presence of many more Clone7 phage in the brain than in the liver, kidney and other internal organs after the nasal administration, suggesting that Clone7 bypassed the blood-brain barrier and entered brain directly. Furthermore, both Clone7 and the ACTTPHAWLCG peptide were found to be heavily distributed along the olfactory nerve after the nasal administration, further suggesting a direct passage route into the brain via the olfactory region. These results demonstrated the feasibility of using the in vivo phage display approach for selecting peptides with the nose-to-brain homing capability and may have implications for the development of novel targeting carriers useful for brain delivery.Part II: Cysteamine (CS) enhanced the chemotherapeutic effect of doxorubicin through autophagy modulation. A previous paper by Brawer et al. reported the occurrence of many Gomori inclusion bodies in CS-treated astrocytes, which would suggest the induction of autophagy. Here we provided a comprehensive line of evidence demonstrating that CS caused autophagosome accumulation in cancer cells. CS exerted a bi-phasic effect on the autophagy process, increasing the formation of autophagosomes in the early phase and blocking the autophagic degradation in a later phase. Furthermore, we showed that CS sensitized doxorubicin-elicited chemotherapeutic killing in HeLa, B16 melanoma and doxorubicin-resistant MCF-7 cells, and also enhanced chemotherapeutic efficacy of doxorubicin in a mouse melanoma model. Finally, we demonstrated that the chemo-sensitizing effect of CS was at least partly dependent on its ability to modulate autophagy, Our results revealed a novel biological function for CS in enhancing the chemotherapeutic effect of doxorubicin through autophagy modulation and pointed to the potential use of CS in adjunct cancer chemotherapy.