Polymer Bulletin

, Volume 74, Issue 6, pp 2159–2184 | Cite as

Synthesis, structural characterization, and antiproliferative/cytotoxic effects of a novel modified poly(maleic anhydride-co-vinyl acetate)/doxorubicin conjugate

  • Gulderen KarakusEmail author
  • Abdulilah Ece
  • Ayse Sahin Yaglioglu
  • Haci Bayram Zengin
  • Mesut Karahan
Original Paper


Drug carrier, poly(maleic anhydride-co-vinyl acetate) (MAVA or poly[MA-co-VA]) copolymer, was traditionally synthesized by free radical chain polymerization reaction, in methyl ethyl ketone (MEK) organic media at 80 °C, using benzoyl peroxide (BPO) as the radicalic initiator. The purified copolymer was then modified with a chemotherapeutic agent, doxorubicin hydrochloride (DOX) at 75 °C for 72 h, using N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) as the carboxylic acid-activating agent. Structural characterization of the MAVA and the modified MAVA/DOX conjugate was carried out by Fourier transform infrared (FTIR) and nuclear magnetic resonance (1H-NMR and 13C-NMR). Their molecular weights were determined by size-exclusion chromatography (SEC). The spectroscopic and SEC results confirmed that conjugated/modification reaction was successfully carried out. UV spectrophotometric measurements indicated that MAVA/DOX preserved its molecular stability in physiological body fluid, PBS (physiological pH 7.40 at 37 °C). Antiproliferative activities of MAVA/DOX were determined by BrdU cell proliferation ELISA assay using C6 (Rat Brain tumor cells) and HeLa (human uterus carcinoma) cell lines in vitro by comparing with free DOX agent (reference compound). Although MAVA showed low antiproliferative activity, both MAVA/DOX and DOX exhibited greater activity against HeLa and C6. Lactate dehydrogenase (LDH) leakage assay was performed for MAVA/DOX and DOX, which detected a non-toxic effect against C6 even at the highest dose (100 μg/mL). IC50 and IC75 values were also determined using ED50 plus v1.0. Molecular modeling at M06-L/6-31 + G(d,p)//AM1 level showed that the electron density in MAVA/DOX is more localized resulting a higher polarization and thereby a higher dipole moment which shed light on the solubility of MAVA/DOX conjugate.

Graphical abstract


Poly(maleic anhydride-co-vinyl acetate) modification Doxorubicin hydrochloride Antiproliferative and cytotoxic activity HeLa and C6 cell lines Computational study Electrostatic potential counter map 



This work was supported by Sciences Research Projects Foundation of Cumhuriyet University (Project No: F258 and F339). Structural characterizations were carried out at Technology Research and Developing Centre, Erciyes University, Kayseri, Turkey. Average molecular weight distribution of MAVA and MAVA/DOX was analyzed by Size-Exclusion Chromatography (SEC) Measurements at Yildiz Technical University.

Compliance with ethical standards

Conflict of interest

The authors of the manuscript solemnly declare that no scientific and/or financial conflicts of interest exist with other people or institutions.


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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Faculty of PharmacyCumhuriyet UniversitySivasTurkey
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyBiruni UniversityIstanbulTurkey
  3. 3.Department of Chemistry, Faculty of ScienceCankırı Karatekin UniversityCankırıTurkey
  4. 4.Department of Chemistry, Faculty of ScienceCumhuriyet UniversitySivasTurkey
  5. 5.Department of Bioengineering, Faculty of Engineering and Natural SciencesÜsküdar UniversityIstanbulTurkey

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