Omega-3 Fatty Acid Grafted PAMAM-Paclitaxel Conjugate Exhibits Enhanced Anticancer Activity in Upper Gastrointestinal Cancer Cells

Abstract

Upper Gastrointestinal Cancers (UGCs) are a leading cause of cancer-related deaths worldwide. Paclitaxel (PTX) is frequently used for the treatment of UGCs; however, low bioavailability, reduced solubility, and dose-dependent toxicity impede its therapeutic use. PAMAMG_4.0 -NH₂ -DHA is synthesized by linking amine-terminated fourth-generation poly(amidoamine) (PAMAMG_4.0 -NH₂ ) dendrimers with omega-3 fatty acid docosahexaenoic acid (DHA). Next, PAMAMG_4.0 -NH₂ -DHA-PTX (DHATX) and PAMAMG_4.0 -NH₂ -PTX (PAX) conjugates are synthesized by subsequent covalent binding of PTX with PAMAMG_4.0 -NH₂ -DHA and PAMAMG_4.0 -NH₂ , respectively. ¹ H-NMR and MALDI-TOF analyses are performed to confirm conjugation of DHA to PAMAMG_4.0 -NH₂ and PTX to PAMAMG_4.0 -NH₂ -DHA. The cell viability, clonogenic cell survival, and flow cytometry analyses are used to determine the anticancer activity of PTX, PAX, and DHATX in UGC cell lines. The in vitro data indicate that treatment with DHATX is significantly more potent than PTX or PAX at inhibiting cellular proliferation, suppressing long-term survival, and inducing cell death in UGC cells.

Keywords: P53 status; cancer therapeutics; dendrimers; paclitaxel; upper gastrointestinal cancers.