[학위논문]항암제 전달을 위한 세포 투과성 펩타이드 기반 약물전달체의 합성과 생물학적 평가 Synthesis and Biological Evaluation of Cell Penetrating Peptide-Based Drug Delivery Vectors for Anticancer Agents원문보기
The cell membrane is an interface between the intracellular and extracellular regions. It permits the entry of only selected drug molecules inside the cells and limits the bioavailability and efficacy as well. This issue has been conquered utilizing cell-penetrating peptides (CPPs). CPPs are identif...
The cell membrane is an interface between the intracellular and extracellular regions. It permits the entry of only selected drug molecules inside the cells and limits the bioavailability and efficacy as well. This issue has been conquered utilizing cell-penetrating peptides (CPPs). CPPs are identified as non-homologous short peptides, consist of 6–30 amino acid residues which can deliver the drug molecules intracellularly with increased efficacy and low cytotoxicity. CPPs expanded the biomedical applications of various drug molecules such as pharmaceutical nanocarriers, proteins, and imaging agents across the cell membrane. Pt-based anticancer drug, oxaliplatin, plays an effective role in colorectal cancer (CRC) treatment but high cytotoxicity, intrinsic drug resistivity, and dose-dependent serious drawbacks restrict its clinical use. These drawbacks can be resolved using drug delivery carriers that can ease the transportation of the drug molecules across the cell membrane. In this work, we designed and conjugated the anticancer drug oxaliplatin to the CPP, octaarginine. The CPP octaarginine plays a significant role as a drug delivery carrier. The conjugate was examined for cytotoxicity, cellular uptake mechanism and localization in various colon cancer cell lines, cellular uptake quantification by tracking Pt metal, and in vivo efficacy using the nude mice model. The conjugate demonstrated far better than oxaliplatin alone in all the cell lines both in vitro and in vivo. Moreover, this drug delivery approach may pave the way for designing improved drug delivery systems in the future. Camptothecin (CPT) and its analogs are among the most effective alkaloids of the 21st century as it is confirmed by their clinical applications. This is the only chemical class that inhibits the enzymatic activity of DNA topoisomerase I (Topo-I), which is responsible for DNA damage and subsequent cellular apoptosis. CPT has some major drawbacks such as extremely poor aqueous solubility, drug resistance by several efflux pumps, and shot half-life, that restricts its clinical uses. To tackle these issues, we designed and prepared a CPP based iRGD-CPT hydrophilic conjugate that successfully delivered CPT into cells. Cytotoxicity evaluations confirmed that iRGD-CPT conjugate reduced the cell viability of cancer cells to a much greater extent than the CPT alone. Cellular localization studies confirmed that CPP iRGD has the potential to improve CPT efficacy because the intensity of fluorescence signals in iRGD-CPT-treated cancer cells was much stronger than CPT-treated and iRGD/CPT-treated cancer cells.
The cell membrane is an interface between the intracellular and extracellular regions. It permits the entry of only selected drug molecules inside the cells and limits the bioavailability and efficacy as well. This issue has been conquered utilizing cell-penetrating peptides (CPPs). CPPs are identified as non-homologous short peptides, consist of 6–30 amino acid residues which can deliver the drug molecules intracellularly with increased efficacy and low cytotoxicity. CPPs expanded the biomedical applications of various drug molecules such as pharmaceutical nanocarriers, proteins, and imaging agents across the cell membrane. Pt-based anticancer drug, oxaliplatin, plays an effective role in colorectal cancer (CRC) treatment but high cytotoxicity, intrinsic drug resistivity, and dose-dependent serious drawbacks restrict its clinical use. These drawbacks can be resolved using drug delivery carriers that can ease the transportation of the drug molecules across the cell membrane. In this work, we designed and conjugated the anticancer drug oxaliplatin to the CPP, octaarginine. The CPP octaarginine plays a significant role as a drug delivery carrier. The conjugate was examined for cytotoxicity, cellular uptake mechanism and localization in various colon cancer cell lines, cellular uptake quantification by tracking Pt metal, and in vivo efficacy using the nude mice model. The conjugate demonstrated far better than oxaliplatin alone in all the cell lines both in vitro and in vivo. Moreover, this drug delivery approach may pave the way for designing improved drug delivery systems in the future. Camptothecin (CPT) and its analogs are among the most effective alkaloids of the 21st century as it is confirmed by their clinical applications. This is the only chemical class that inhibits the enzymatic activity of DNA topoisomerase I (Topo-I), which is responsible for DNA damage and subsequent cellular apoptosis. CPT has some major drawbacks such as extremely poor aqueous solubility, drug resistance by several efflux pumps, and shot half-life, that restricts its clinical uses. To tackle these issues, we designed and prepared a CPP based iRGD-CPT hydrophilic conjugate that successfully delivered CPT into cells. Cytotoxicity evaluations confirmed that iRGD-CPT conjugate reduced the cell viability of cancer cells to a much greater extent than the CPT alone. Cellular localization studies confirmed that CPP iRGD has the potential to improve CPT efficacy because the intensity of fluorescence signals in iRGD-CPT-treated cancer cells was much stronger than CPT-treated and iRGD/CPT-treated cancer cells.
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