A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC
Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with...
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MDPI AG
2023-01-01
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| Series: | BioTech |
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| Online Access: | https://www.mdpi.com/2673-6284/12/1/13 |
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| author | Zally Torres-Martinez Daraishka Pérez Grace Torres Sthephanie Estrada Clarissa Correa Natasha Mederos Kimberly Velazquez Betzaida Castillo Kai Griebenow Yamixa Delgado |
| author_facet | Zally Torres-Martinez Daraishka Pérez Grace Torres Sthephanie Estrada Clarissa Correa Natasha Mederos Kimberly Velazquez Betzaida Castillo Kai Griebenow Yamixa Delgado |
| author_sort | Zally Torres-Martinez |
| collection | DOAJ |
| description | Nanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene that has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds, doxorubicin (Dox) and the triterpene BeA, using an oil-water-like micro-emulsion method. We used spectrophotometric assays to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy, confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h at pH 6.8, while less drug was released at pH 7.4 in this period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against non-small-cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA-(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed the cellular internalization of the DDS and the accumulation of the Dox in the nucleus. We determined the mechanism of action of the BSA-(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC. |
| first_indexed | 2024-03-11T06:51:20Z |
| format | Article |
| id | doaj.art-2d1c01b939b84995a3399d63aa30b6de |
| institution | Directory Open Access Journal |
| issn | 2673-6284 |
| language | English |
| last_indexed | 2024-03-11T06:51:20Z |
| publishDate | 2023-01-01 |
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| series | BioTech |
| spelling | doaj.art-2d1c01b939b84995a3399d63aa30b6de2023-11-17T09:55:11ZengMDPI AGBioTech2673-62842023-01-011211310.3390/biotech12010013A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLCZally Torres-Martinez0Daraishka Pérez1Grace Torres2Sthephanie Estrada3Clarissa Correa4Natasha Mederos5Kimberly Velazquez6Betzaida Castillo7Kai Griebenow8Yamixa Delgado9Chemistry Department, University of Puerto Rico, Rio Piedras Campus, San Juan 00925, Puerto RicoNeuroscience Department, Universidad Central del Caribe, Bayamon 00960, Puerto RicoBiochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto RicoBiology Department, University of Puerto Rico—Cayey, Cayey 00736, Puerto RicoBiochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto RicoBiochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto RicoBiochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto RicoChemistry Department, University of Puerto Rico—Humacao, Humacao 00727, Puerto RicoChemistry Department, University of Puerto Rico, Rio Piedras Campus, San Juan 00925, Puerto RicoBiochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto RicoNanosized drug delivery systems (DDS) have been studied as a novel strategy against cancer due to their potential to simultaneously decrease drug inactivation and systemic toxicity and increase passive and/or active drug accumulation within the tumor(s). Triterpenes are plant-derived compounds with interesting therapeutic properties. Betulinic acid (BeA) is a pentacyclic triterpene that has great cytotoxic activity against different cancer types. Herein, we developed a nanosized protein-based DDS of bovine serum albumin (BSA) as the drug carrier combining two compounds, doxorubicin (Dox) and the triterpene BeA, using an oil-water-like micro-emulsion method. We used spectrophotometric assays to determine protein and drug concentrations in the DDS. The biophysical properties of these DDS were characterized using dynamic light scattering (DLS) and circular dichroism (CD) spectroscopy, confirming nanoparticle (NP) formation and drug loading into the protein structure, respectively. The encapsulation efficiency was 77% for Dox and 18% for BeA. More than 50% of both drugs were released within 24 h at pH 6.8, while less drug was released at pH 7.4 in this period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against non-small-cell lung carcinoma (NSCLC) A549 cells. Viability assays of the BSA-(Dox+BeA) DDS demonstrated a higher synergistic cytotoxic activity than the two drugs with no carrier. Moreover, confocal microscopy analysis confirmed the cellular internalization of the DDS and the accumulation of the Dox in the nucleus. We determined the mechanism of action of the BSA-(Dox+BeA) DDS, confirming S-phase cell cycle arrest, DNA damage, caspase cascade activation, and downregulation of epidermal growth factor receptor (EGFR) expression. This DDS has the potential to synergistically maximize the therapeutic effect of Dox and diminish chemoresistance induced by EGFR expression using a natural triterpene against NSCLC.https://www.mdpi.com/2673-6284/12/1/13betulinic acidbovine serum albumindoxorubicindrug delivery systemlung cancersynergistic effect |
| spellingShingle | Zally Torres-Martinez Daraishka Pérez Grace Torres Sthephanie Estrada Clarissa Correa Natasha Mederos Kimberly Velazquez Betzaida Castillo Kai Griebenow Yamixa Delgado A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC BioTech betulinic acid bovine serum albumin doxorubicin drug delivery system lung cancer synergistic effect |
| title | A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC |
| title_full | A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC |
| title_fullStr | A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC |
| title_full_unstemmed | A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC |
| title_short | A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC |
| title_sort | synergistic ph responsive serum albumin based drug delivery system loaded with doxorubicin and pentacyclic triterpene betulinic acid for potential treatment of nsclc |
| topic | betulinic acid bovine serum albumin doxorubicin drug delivery system lung cancer synergistic effect |
| url | https://www.mdpi.com/2673-6284/12/1/13 |
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