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Theranostics 2024; 14(8):3221-3245. doi:10.7150/thno.95476 This issue Cite

Research Paper

Discovery of 2-deoxy glucose surfaced mixed layer dendrimer: a smart neuron targeted systemic drug delivery system for brain diseases

Anubhav Dhull^1#, Zhi Zhang^2#, Rishi Sharma^1#, Aqib Iqbal Dar¹, Anu Rani¹, Jing Wei³, Shamila Gopalakrishnan¹, Amanda Ghannam², Victoria Hahn², Anunay James Pulukuri¹, Stefanie Tasevski², Sara Moughni², Boyang Jason Wu³, Anjali Sharma^1✉

1. Department of Chemistry, College of Arts and Sciences, Washington State University, 1470 NE College Ave, Pullman, WA, USA 99164.
2. Department of Natural Sciences, College of Arts, Sciences, and Letters, University of Michigan -Dearborn, 4901 Evergreen Rd, Dearborn, MI, USA 48128.
3. Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA 99202.
^#These authors contributed equally to this work.

✉ Corresponding author: Anjali Sharma, Department of Chemistry, Washington State University, Troy Hall, Rm 222, 1470 E. College Avenue, Pullman, WA 99164, USA. E-mail: anjali.sharmaedu.

Abstract

The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process.

Methods: In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer (2DG-D) utilizing biocompatible and cost-effective materials via a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of 2DG-D, and brain delivery of a neuroprotective agent pioglitazone (Pio) in a pediatric traumatic brain injury (TBI) model.

Results: The 2DG-D exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the 2DG-D localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers Pio, ameliorates neuroinflammation, and improves behavioral outcomes.

Conclusions: The promising in vivo results coupled with a convenient synthetic approach for the construction of 2DG-D makes it a potential nanoplatform for addressing brain diseases.

Keywords: neuron targeting, non-invasive brain targeting, nanotherapeutics, dendrimer, drug conjugate, targeted drug delivery

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