Carboxylic Acid- and Amine-Modified Pluronic F127-Based Thermoresponsive Nanogels as Smart Carriers for Brain Drug Delivery.

Abstract

<h4>Introduction</h4>The blood-brain barrier (BBB) is a critical protective barrier that regulates the exchange of substances between the circulatory system and brain, restricting the access of drugs to brain tissues. Developing novel delivery strategies across the BBB is challenging but crucial. Multifunctional nanogels are promising drug carriers for delivering therapeutic agents to their intended target areas in the brain tissue.<h4>Methods</h4>This study introduced carboxylic acid- and amine-modified Pluronic F127 (ADF127 and EDF127)-based thermoresponsive nanogel systems as drug nanocarriers for brain tissues. The release profiles of 3-butylidenephthalide (BP) from the nanogels were investigated in vitro in phosphate-buffered saline (pH 7.4) at 37 °C for 48 h. Additionally, the accumulation of DiR-labeled nanogels in vital organs was observed using fluorescence imaging.<h4>Results</h4>A relatively sustained BP release (27%) from ADF127, followed by rapid BP release (39%) from Pluronic F127 within the first 4 h were observed. In vivo studies using the C57BL/6JNarl mouse model showed that intravenously administered BP-loaded copolymeric nanogels exhibited a rapid BP distribution to the liver, spleen, heart, and kidney. DiR fluorescence intensity in the brain increased in the order Pluronic F127 < ADF127 < EDF127 copolymeric nanogels. Although the fluorescence intensity of DiR in the brain tissue was relatively lower than those in other vital organs, the DiR-labeled EDF127 copolymeric nanogels showed approximately 10-fold higher fluorescence intensity.<h4>Conclusion</h4>Positively charged drug carrier nanomaterials demonstrate a higher propensity for transfer through the BBB, significantly expanding the applicability of positively charged EDF127 nanogels as nanocarriers for in vivo brain tissue treatment and imaging. Therefore, owing to their increased permeability across the BBB, carboxylic acid- and amine-modified Pluronic F127 nanogels (EDF127 and ADF127) will also offer a promising approach for brain tissue treatment and imaging.