Folic Acid Conjugated δ-Valerolactone-Poly(ethylene glycol) Based Triblock Copolymer as a Promising Carrier for Targeted Doxorubicin Delivery

Abstract

The aim of this study is to test the hypothesis that the newly synthesized poly(δ-valerolactone)/poly(ethylene glycol)/poly(δ-valerolactone) (VEV) copolymer grafted with folic acid would impart targetability and further enhance the anti-tumor efficacy of doxorubicin (DOX). Here, folic acid conjugated VEV (VEV-FOL) was synthesized by a modified esterification method and characterized using IR and NMR. DOX loaded VEV-FOL micelles were synthesized using a novel solvent evaporation method and were obtained with a mean diameter of 97 nm with high encapsulation efficiency and sustained in vitro release profile. Comparative studies of polymer micelles with and without folate for cellular uptake and cytotoxicity were done on folate receptor-positive breast cancer cell line, MDAMB231. The intracellular uptake tests showed significant increase in folate micellar uptake when compared to non-folate-mediated micelles. MTT assay followed by apoptosis assays clearly indicated that folate decorated micelles showed significantly better cytotoxicity (IC50 = 0.014 µM) and efficiency to induce apoptosis than other treated groups. Moreover, a significant G2/M arrest was induced by DOX loaded VEV-FOL micelles at a concentration where free drug failed to show any activity. Thus, our results show that the folic acid-labeled VEV copolymer is a promising biomaterial with controlled and sustainable tumor targeting ability for anticancer drugs which can open new frontiers in the area of targeted chemotherapy.

Novel Insights Into Appropriate Encapsulation Methods for Bioactive Compounds Into Polymers: A Study With Peptides and HDAC Inhibitors

“…Thus, the studies and, in turn, literature reports on drug delivery systems employing nanoparticle‐techniques are dominated (>60%) by the use of low‐molar‐mass drugs. This can be exemplified with drugs such as the nucleobase and/or nucleoside analogs acyclovir, cytarabine, and 5‐fluorouracil, local anesthetic benzocaine, non‐opioid analgesic diclofenac and diuretic furosemide …”

Oral Delivery of Multicompartment Nanomedicines for Colorectal Cancer Therapeutics: Combining Loco‐Regional Delivery with Cell‐Target Specificity

“…This modification was confirmed using 1 H NMR (Figure S2A, Supporting Information) which showed the appearance of new peaks at 3.1 ppm (methylene peak adjacent to alcohol group) and 3.8 ppm (methylene peak adjacent to amide group). Following this, the modified HA was reacted with the polymer containing carboxylic acid end‐groups via a Steglich esterification reaction to form 4 . Following purification, HA conjugation was confirmed using 1 H NMR which showed the presence of a broad peak appearing at 4.4 to 4.6 ppm post‐conjugation, which is due to the free hydroxyl groups of HA ( Figure 1A).…”

“…Following this, the modified HA was reacted with the polymer containing carboxylic acid end-groups via a Steglich esterification reaction to form 4. [28] Following purification, HA conjugation was confirmed using 1 H NMR which showed the presence of a broad peak appearing at 4.4 to 4.6 ppm post-conjugation, which is due to the free hydroxyl groups of HA ( Figure 1A). Confirmation of conjugation was also determined using diffusion ordered spectroscopy (DOSY) NMR, whereby only a single diffusing signal was observed for the final compound ( Figure 1B).…”

Sulfated polysaccharide-protein complex sensitizes doxorubicin-induced apoptosis of breast cancer cells in vitro and in vivo

“…Apoptosis was assessed by measuring the membrane redistribution of phosphatidylserine using an Annexin V-Fluorescein Isothiocyanate (FITC) Apoptosis Detection kit (BD Pharmingen, San Diego, CA, USA), according to the manufacturer's protocol. Briefly, cells were incubated with 1 µM DOX, 5 µM SPPC or both for 24 h. (22,23), and the cells were collected and washed twice with PBS followed by resuspension in 500 µl staining solution containing FITC-conjugated Annexin V antibody (5 µl) and PI (250 µg/ml stock solution). Following incubation at 37˚C in the dark for 15 min, the cells were analyzed by flow cytometry.…”