Effect of Glucosamine Conjugate-Functionalized Liposomes on Glioma Cell and Healthy Brain: An Insight for Future Applica
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Research Article Effect of Glucosamine Conjugate-Functionalized Liposomes on Glioma Cell and Healthy Brain: An Insight for Future Application in Brain Infusion Nisha Yadav,1 Jacinth Rajendra,2,3 Anagha Acharekar,2,3 Shilpee Dutt,2,3 and Pradeep Vavia1,4
Received 5 July 2019; accepted 7 October 2019 Abstract. Conjugation of D-glucosamine with lipophilic moiety can ease its application in surface modification of liposomes. Interestingly, although D-glucosamine is safe, studies have shed light on “toxic effect” of its conjugates on cancer cells and highlighted its application in targeting glioma. However, understanding the safety of such conjugates for local delivery to the brain is unavailable. Herein, after successful synthesis of D-glucosamine conjugate (GC), the toxicity of functionalized liposome was evaluated both in vitro and in vivo. The study revealed a significant effect on cytotoxicity and apoptosis in vitro as assessed on grade IVresistant glioma cell lines, SF268, U87MG, using MTT assay and PI staining. Additionally, this effect was not observed on normal human erythrocytes in the hemolysis assay. Furthermore, we demonstrated that GC liposomes were non-toxic to the normal brain tissues of healthy Sprague-Dawley rats. Successful functionalization yielded liposome with uniform particle size, stability, and cellular uptake. With < 10% hemolysis, all the liposomal formulations demonstrated hemato-compatibility but led to high glioma cytotoxicity. The surface density of conjugate played an important role in tumor toxicity (0.5 < 1.0 ≤ 2.0% molar ratio). PI staining revealed that compared to control cell, functionalization led 26-fold increase in induction of apoptosis in glioma cells. Absence of histological and behavioral changes along with the absence of caspase-3 in brain tissue confirmed the suitability of the system for direct infusion in the brain. Thus, this study will aid the future development of clinically useful local chemotherapeutic without “add-in” side effects. KEY WORDS: nanotoxicology; glucosamine conjugate; surface density; brain infusion; selective toxicity.
INTRODUCTION Glucosamine is a naturally occurring amino monosaccharide which is obtained by either chemical or enzymatic hydrolysis of chitin and chitosan (1). Recently, there has been research for exploring this amino sugar due to its usages in inducing autophagy in glioma cells and targeting of cancer cells (2,3). Application of well-known conjugation technique to synthesize D-glucosamine conjugate (GC) can ease the Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12249-019-1567-9) contains supplementary material, which is available to authorized users. 1
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, University Under Section 3 of UGC Act—1956, Elite Status and Center of Excellence—Govt. of Maharashtra, TEQIP Phase II Funded, Mumbai, 400019, India. 2 Shilpee’s Lab., Cancer Research Institute, Advanced Center for Treatment, Research and Education in C
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