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A Synergistic pH-Responsive serum albumin-based drug delivery system loaded with doxorubicin and pentacyclic triterpene betulinic acid for potential treatment of NSCLC
Torres-Martinez, Z.; Pérez, D.; Torres, G.; Estrada, S.; Correa, C.; Mederos, N.; Velazquez, K.; Castillo, B.; Griebenow, K.; Delgado, Y. A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC. BioTech2023, 12, 13.
Torres-Martinez, Z.; Pérez, D.; Torres, G.; Estrada, S.; Correa, C.; Mederos, N.; Velazquez, K.; Castillo, B.; Griebenow, K.; Delgado, Y. A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC. BioTech 2023, 12, 13.
Torres-Martinez, Z.; Pérez, D.; Torres, G.; Estrada, S.; Correa, C.; Mederos, N.; Velazquez, K.; Castillo, B.; Griebenow, K.; Delgado, Y. A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC. BioTech2023, 12, 13.
Torres-Martinez, Z.; Pérez, D.; Torres, G.; Estrada, S.; Correa, C.; Mederos, N.; Velazquez, K.; Castillo, B.; Griebenow, K.; Delgado, Y. A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC. BioTech 2023, 12, 13.
Abstract
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 which 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. Spectrophotometric assays were performed 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 time period. Co-incubation viability assays of Dox and BeA alone for 24 h demonstrated synergistic cytotoxic activity in the low μM range against the 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 cellular internalization of the DDS and nucleus accumulation of the Dox. 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 the 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.
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