Chitosan Engineered PAMAM Dendrimers as Nanoconstructs for the Enhanced Anti-Cancer Potential and Improved In vivo Brain Pharmacokinetics of Temozolomide

Abstract

Purpose: To establish a platform for the possibility of effective and safe delivery of Temozolomide (TMZ) to brain via surface engineered (polyamidoamine) PAMAM dendrimer for the treatment of glioblastoma.

Methods: The present study aims to investigate the efficacy of PAMAM-chitosan conjugate based TMZ nanoformulation (PCT) against gliomas in vitro as well as in vivo. The prepared nanoconjugated formulation was characterized by ¹H NMR, FT-IR spectroscopy and for surface morphological parameters. The reported approach was also designed in such a way to ensure toxicity before in vivo delivery through conducting the hemolytic study.

Result: Surface morphology was found as per nanoformulation via size, pdi and zeta potential measurement. PCT was more efficacious in terms of IC₅₀ values compared to pure TMZ against U-251 and T-98G glioma cell lines. The in vivo pharmacokinetic parameters proved sustained release fashion such as half-life (t_1/2) of 22.74 h (PCT) rather than15.35 h (TMZ) only. Higher concentration was found in heart than brain in bio-distribution studies. This study exhibits the potential applicability of dendrimer and CS in improving the anticancer activity and delivery of TMZ to brain.

Conclusion: The attractive ex vivo cytotoxicity against two glioma cell lines; U-251 and T-98G and phase solubility studies of TMZ revealed remarkable results. In vivo studies of prepared nanoformulation were significant and promising that explored the double concentration of TMZ in brain due to surface functionality of dendrimer. The reported work is novel and non- obvious as none of such approaches using chitosan anchored dendrimer for TMZ delivery has been reported earlier.

Keywords: PAMAM; TMZ; bio-distribution; brain delivery; chitosan; solubility.