Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine
One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug appr...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2017-08-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/22/8/1322 |
| _version_ | 1818266860053856256 |
|---|---|
| author | Yasuhiro Tsume Adam J. Drelich David E. Smith Gordon L. Amidon |
| author_facet | Yasuhiro Tsume Adam J. Drelich David E. Smith Gordon L. Amidon |
| author_sort | Yasuhiro Tsume |
| collection | DOAJ |
| description | One of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs. |
| first_indexed | 2024-12-12T20:13:24Z |
| format | Article |
| id | doaj.art-d164940f608d44c8b023beacb3280a9e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-12T20:13:24Z |
| publishDate | 2017-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-d164940f608d44c8b023beacb3280a9e2022-12-22T00:13:27ZengMDPI AGMolecules1420-30492017-08-01228132210.3390/molecules22081322molecules22081322Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of GemcitabineYasuhiro Tsume0Adam J. Drelich1David E. Smith2Gordon L. Amidon3Department of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USADepartment of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USADepartment of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USADepartment of Pharmaceutical Science, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109-1065, USAOne of the main obstacles for cancer therapies is to deliver medicines effectively to target sites. Since stroma cells are developed around tumors, chemotherapeutic agents have to go through stroma cells in order to reach tumors. As a method to improve drug delivery to the tumor site, a prodrug approach for gemcitabine was adopted. Amino acid and dipeptide monoester prodrugs of gemcitabine were synthesized and their chemical stability in buffers, resistance to thymidine phosphorylase and cytidine deaminase, antiproliferative activity, and uptake/permeability in HFF cells as a surrogate to stroma cells were determined and compared to their parent drug, gemcitabine. The activation of all gemcitabine prodrugs was faster in pancreatic cell homogenates than their hydrolysis in buffer, suggesting enzymatic action. All prodrugs exhibited great stability in HFF cell homogenate, enhanced resistance to glycosidic bond metabolism by thymidine phosphorylase, and deamination by cytidine deaminase compared to their parent drug. All gemcitabine prodrugs exhibited higher uptake in HFF cells and better permeability across HFF monolayers than gemcitabine, suggesting a better delivery to tumor sites. Cell antiproliferative assays in Panc-1 and Capan-2 pancreatic ductal cell lines indicated that the gemcitabine prodrugs were more potent than their parent drug gemcitabine. The transport and enzymatic profiles of gemcitabine prodrugs suggest their potential for delayed enzymatic bioconversion and enhanced resistance to metabolic enzymes, as well as for enhanced drug delivery to tumor sites, and cytotoxic activity in cancer cells. These attributes would facilitate the prolonged systemic circulation and improved therapeutic efficacy of gemcitabine prodrugs.https://www.mdpi.com/1420-3049/22/8/1322gemcitabine prodrugsstroma cellspancreatic cancermetabolismcytosine deaminase |
| spellingShingle | Yasuhiro Tsume Adam J. Drelich David E. Smith Gordon L. Amidon Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine Molecules gemcitabine prodrugs stroma cells pancreatic cancer metabolism cytosine deaminase |
| title | Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine |
| title_full | Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine |
| title_fullStr | Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine |
| title_full_unstemmed | Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine |
| title_short | Potential Development of Tumor-Targeted Oral Anti-Cancer Prodrugs: Amino Acid and Dipeptide Monoester Prodrugs of Gemcitabine |
| title_sort | potential development of tumor targeted oral anti cancer prodrugs amino acid and dipeptide monoester prodrugs of gemcitabine |
| topic | gemcitabine prodrugs stroma cells pancreatic cancer metabolism cytosine deaminase |
| url | https://www.mdpi.com/1420-3049/22/8/1322 |
| work_keys_str_mv | AT yasuhirotsume potentialdevelopmentoftumortargetedoralanticancerprodrugsaminoacidanddipeptidemonoesterprodrugsofgemcitabine AT adamjdrelich potentialdevelopmentoftumortargetedoralanticancerprodrugsaminoacidanddipeptidemonoesterprodrugsofgemcitabine AT davidesmith potentialdevelopmentoftumortargetedoralanticancerprodrugsaminoacidanddipeptidemonoesterprodrugsofgemcitabine AT gordonlamidon potentialdevelopmentoftumortargetedoralanticancerprodrugsaminoacidanddipeptidemonoesterprodrugsofgemcitabine |