Surface-engineered dendrimers for dual drug delivery: A receptor up-regulation and enhanced cancer targeting strategy

Abstract

The present study is aimed at developing and evaluating a combined strategy of dual drug delivery, receptor up-regulation, and drug targeting. The dendritic architectures were synthesized and characterized by IR, ¹H-NMR, and ¹³C-NMR spectroscopy. The pH-responsive simultaneous release behavior of the loaded bioactive from the carrier was also explored. The cell line studies for MTT cytotoxicity, receptor blockade, and receptor up-regulation assays were performed on HeLa cells. Treatment of cells with low concentration of all-trans retinoic acid (ATRA, ∼1 μM) caused a selective up-regulation of folate receptors by 2.21-folds when compared with that of untreated control, after 48 h. ATRA showed a lag phase of 12 h in up-regulating the folate receptors. After 48 h, the IC₅₀ value of naked methotrexate (MTX)–ATRA combination and dendrimer-loaded MTX–ATRA combination were found to be ∼0.1 and 10 μM, respectively, while folate-anchored dendrimer loaded with MTX–ATRA showed a selectively lowered IC₅₀ value of 0.04 μM. It was concluded that in allied ailments like cancer, the proposed dual-drug delivery modality bearing anti-cancer bioactive in conjunction with folate receptor up-regulating cargo may prove to be a promising approach toward the development of a flourishing cancer therapy.

Keywords::

• Dual drug therapy
• folate-based targeting
• receptor up-regulation
• MTT cytotoxicity
• receptor up-regulation assay

Acknowledgements

The authors (Rakesh K. Tekade and Tathagata Dutta) would like to thank All India Council of Technical Education (AICTE), New Delhi, and Indian Council of Medical Research (ICMR), New Delhi (India), respectively, for providing the financial assistance. The authors are also grateful to Institute of Cytology and Preventive Oncology, Indian Council of Medical Research, Noida (UP), India, for extending facilities to perform ex vivo studies on cancer cell lines. The authors would also like to acknowledge Shalaks Pharmaceuticals (P) Ltd, New Delhi, India, and M/s Dabur Research Foundation, Hyderabad, India, for providing the gift samples of ATRA and MTX, respectively.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.