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Selective protein delivery to acidic tumor and inflammatory microenvironment by pH sensitive linker application

Title
Selective protein delivery to acidic tumor and inflammatory microenvironment by pH sensitive linker application
Other Titles
pH 반응성 가교 서열을 이용한 산성 암 미세환경 혹은 염증 조직에 대한 선택적 단백질 전달 연구
Author
Donghun Cha
Alternative Author(s)
차동훈
Advisor(s)
최제민
Issue Date
2019-02
Publisher
한양대학교
Degree
Master
Abstract
Inflammatory region and tumor microenvironment (TME) have lower pH than normal tissues due to increased cell density to produce acidic waste. Therefore, a targeting strategy for acidic microenvironment to specific drug distribution in vivo could be considered with a CPP (cell-permeable peptide) mediate protein delivery in tumor or inflammatory disease model. Here, we designed pH sensitive linker (HE) which could attenuate a CPP function by charge interaction. We generated a recombinant protein containing pH-sensitive linker and AP (Astrotactin 1–derived peptide)-CPP and screened its protein delivery efficiency in various pH environment. In vitro, we optimized proper pH sensitive sequence (AP-10HE) and confirmed that the protein delivery efficiency was increased pH 6.5 or 6 than 7.4 in several cell lines like Hela, U271, U343, Hacat. Next, we would like to confirm pH linker prevent AP-dTomato protein delivery in liver, kidney, spleen tissue in normal mice and hypothesized it could be more specific in tumor or diseased tissue. We found AP-10HE shows specific delivery to tumor region in subcutaneously implanted B16F10 cells of mice and it also specifically delivered in spinal cord tissue rather than liver or kidney in EAE (Experimental autoimmune encephalomyelitis) model. These results suggest that the pH sensitive linker combined to AP-CPP could be a specific targeting tool for delivering of biologic drug like a protein into acidic microenvironment, so could be utilized for tumor therapy or immune modulatory drug development research.
URI
http://dcollection.hanyang.ac.kr/common/orgView/000000108925http://repository.hanyang.ac.kr/handle/20.500.11754/99334
Appears in Collections:
GRADUATE SCHOOL[S](대학원) > LIFE SCIENCE(생명과학과) > Theses (Master)
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