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Novel chlorambucil-conjugated anionic linear-globular PEG-based second-generation dendrimer: in vitro/in vivo improved anticancer activity

Authors Assadi A, Sharifi Najafabadi V, Shandiz AS, Shayeq Boroujeni A, Ashrafi S, Zaman Vaziri A, Ghoreishi SM, Aghasadeghi M, Sadat Ebrahimi SE, Pirali-Hamedani M, Shafiee Ardestani M

Received 2 January 2016

Accepted for publication 22 April 2016

Published 7 September 2016 Volume 2016:9 Pages 5531—5543


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Lucy Goodman

Peer reviewer comments 4

Editor who approved publication: Dr Faris Farassati

Artin Assadi,1 Vahideh Sharifi Najafabadi,1 Seyed Ataollah Sadat Shandiz,2 Azadah Shayeq Boroujeni,1 Sepehr Ashrafi,1 Ali Zaman Vaziri,1 Seyedeh Masoumeh Ghoreishi,1 Mohammad Reza Aghasadeghi,3 Seyed Esmaeil Sadat Ebrahimi,4 Morteza Pirali-Hamedani,4 Mehdi Shafiee Ardestani1

1Department of Radiopharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, 2Young Researchers and Elite Club, East Tehran Branch, Islamic Azad University, 3Department of Hepatitis and AIDS, Pasteur Institute of Iran, 4Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Abstract: Evaluating the efficacy of anticancer drugs is an evolving and research-oriented issue. The objective of this study was to reduce the insolubility of chlorambucil (CBL) in water and improve the anticancer activity of CBL in vitro and in vivo through the conjugation of CBL with anionic linear-globular dendrimer (second generation, G2). In the current study, the anticancer activity among three groups that include CBL, CBL–G2 dendrimer, and control was measured in vitro and in vivo. In vitro studies showed that G2 anionic linear-globular polyethylene-glycol-based dendrimer, which conjugated to the CBL exterior through an ester linkage, was able to significantly improve the treatment efficacy over clinical CBL alone with respect to proliferation assay, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide; half maximal inhibitory concentration (IC50) was calculated to be 141 µg/mL for CBL alone and 27.7 µg/mL for CBL–G2 dendrimer; P<0.05. In addition, CBL–G2 dendrimer conjugate forestalled the growth of MCF-7 cancerous cells in addition to enhancing the number of apoptotic and necrotic cells as demonstrated by an annexin V-fluorescein isothiocyanate assay. CBL–G2 dendrimer conjugate was able to checkmate antiapoptotic Bcl-2 expression and Bcl-2/Bax ratio in a large scale compared with the control group and CBL alone (P<0.005). In vivo studies showed that tumor treatment by CBL–G2 dendrimer conjugate outstrips the efficacy of treatment compared with CBL alone. The evaluation was based on reduction in tumor volume and tumor growth inhibition of murine 4T1 mammary tumor cells. Tumor volume of 140%±8% was measured in the treatment with CBL–G2 dendrimer, whereas 152%±13.5% was calculated in the treatment with free CBL (P<0.05). However, there were no significant differences in histological assay among the three groups. In conclusion, tumor growth suppression potential of CBL–G2 dendrimer, which was assessed in both in vitro and in vivo experiments, has provided empirical evidence to buttress the fact that this compound could be considered for functional cancer treatment with low side effects.

Keywords: anionic linear-globular dendrimer, G2, chlorambucil, CBL, in vitro cytotoxicity, in vivo efficacy

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