Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity
Hai V Ngo,1 Hye-Eun Bak,1 Hy D Nguyen,1 Kye Wan Lee,2 Chulhun Park,3 Beom-Jin Lee1 1College of Pharmacy, Ajou University, Suwon, 16499 Republic of Korea; 2Dongkook Pharmaceutical Co., Ltd., Seoul, 06072 Republic of Korea; 3College of Pharmacy, Jeju National University, Jeju, 63243 Republic of KoreaC...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2023-05-01
|
| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/physicochemical-and-biopharmaceutical-controllability-of-new-self-asse-peer-reviewed-fulltext-article-IJN |
| _version_ | 1797833266628132864 |
|---|---|
| author | Ngo HV Bak HE Nguyen HD Lee KW Park C Lee BJ |
| author_facet | Ngo HV Bak HE Nguyen HD Lee KW Park C Lee BJ |
| author_sort | Ngo HV |
| collection | DOAJ |
| description | Hai V Ngo,1 Hye-Eun Bak,1 Hy D Nguyen,1 Kye Wan Lee,2 Chulhun Park,3 Beom-Jin Lee1 1College of Pharmacy, Ajou University, Suwon, 16499 Republic of Korea; 2Dongkook Pharmaceutical Co., Ltd., Seoul, 06072 Republic of Korea; 3College of Pharmacy, Jeju National University, Jeju, 63243 Republic of KoreaCorrespondence: Beom-Jin Lee, College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea, Email bjl@ajou.ac.krBackground: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity.Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs).Methods: LEU–fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3.Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days.Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.Graphical Abstract: Keywords: leuprolide, fattigation, fatty acid chain length, LEU–fatty acid conjugate, self-assembled nanoparticles, enhanced permeability, improved anticancer activity |
| first_indexed | 2024-04-09T14:20:27Z |
| format | Article |
| id | doaj.art-403fc23047694850808c705b988b5913 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-04-09T14:20:27Z |
| publishDate | 2023-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-403fc23047694850808c705b988b59132023-05-04T19:14:20ZengDove Medical PressInternational Journal of Nanomedicine1178-20132023-05-01Volume 182325234483493Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer ActivityNgo HVBak HENguyen HDLee KWPark CLee BJHai V Ngo,1 Hye-Eun Bak,1 Hy D Nguyen,1 Kye Wan Lee,2 Chulhun Park,3 Beom-Jin Lee1 1College of Pharmacy, Ajou University, Suwon, 16499 Republic of Korea; 2Dongkook Pharmaceutical Co., Ltd., Seoul, 06072 Republic of Korea; 3College of Pharmacy, Jeju National University, Jeju, 63243 Republic of KoreaCorrespondence: Beom-Jin Lee, College of Pharmacy, Ajou University, Suwon, 16499, Republic of Korea, Email bjl@ajou.ac.krBackground: Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity.Purpose: To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs).Methods: LEU–fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3.Results: Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days.Conclusion: The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.Graphical Abstract: Keywords: leuprolide, fattigation, fatty acid chain length, LEU–fatty acid conjugate, self-assembled nanoparticles, enhanced permeability, improved anticancer activityhttps://www.dovepress.com/physicochemical-and-biopharmaceutical-controllability-of-new-self-asse-peer-reviewed-fulltext-article-IJNleuprolidefattigationfatty acid chain lengthleu-fatty acid conjugateself-assembled nanoparticlesenhanced permeabilityimproved anticancer activity |
| spellingShingle | Ngo HV Bak HE Nguyen HD Lee KW Park C Lee BJ Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity International Journal of Nanomedicine leuprolide fattigation fatty acid chain length leu-fatty acid conjugate self-assembled nanoparticles enhanced permeability improved anticancer activity |
| title | Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity |
| title_full | Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity |
| title_fullStr | Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity |
| title_full_unstemmed | Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity |
| title_short | Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity |
| title_sort | physicochemical and biopharmaceutical controllability of new self assembled fatty acid conjugated leuprolide for the enhanced anticancer activity |
| topic | leuprolide fattigation fatty acid chain length leu-fatty acid conjugate self-assembled nanoparticles enhanced permeability improved anticancer activity |
| url | https://www.dovepress.com/physicochemical-and-biopharmaceutical-controllability-of-new-self-asse-peer-reviewed-fulltext-article-IJN |
| work_keys_str_mv | AT ngohv physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity AT bakhe physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity AT nguyenhd physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity AT leekw physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity AT parkc physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity AT leebj physicochemicalandbiopharmaceuticalcontrollabilityofnewselfassembledfattyacidconjugatedleuprolidefortheenhancedanticanceractivity |