A Synergistic pH-Responsive Serum Albumin-Based Drug Delivery System Loaded with Doxorubicin and Pentacyclic Triterpene Betulinic Acid for Potential Treatment of NSCLC

Author:

Torres-Martinez Zally1,Pérez Daraishka2,Torres Grace3,Estrada Sthephanie4,Correa Clarissa3,Mederos Natasha3,Velazquez Kimberly3,Castillo Betzaida5,Griebenow Kai1,Delgado Yamixa3ORCID

Affiliation:

1. Chemistry Department, University of Puerto Rico, Rio Piedras Campus, San Juan 00925, Puerto Rico

2. Neuroscience Department, Universidad Central del Caribe, Bayamon 00960, Puerto Rico

3. Biochemistry & Pharmacology Department, San Juan Bautista School of Medicine, Caguas 00727, Puerto Rico

4. Biology Department, University of Puerto Rico—Cayey, Cayey 00736, Puerto Rico

5. Chemistry Department, University of Puerto Rico—Humacao, Humacao 00727, Puerto Rico

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 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.

Funder

National Institutes of Health

Sloan Scholars Mentoring Network Seed Grant and Fundación Intellectus

Neuroimaging and Electrophysiology Facility

Publisher

MDPI AG

Subject

Applied Microbiology and Biotechnology,Biomedical Engineering,Biochemistry,Bioengineering,Biotechnology

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