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

WHOM among the incompetent idiots in the stroke medical world can look at this and suggest maybe safer clot busting delivery? Reduced bolus of both alteplase and Tenecteplase vastly reducing the hemorrhage risk. Well, if you're not idiots you can tell me EXACTLY where I'm wrong: oc1dean@gmail.com, Looking forward to your hate mail.

Oops, I'm not playing by the polite rules of Dale Carnegie,  'How to Win Friends and Influence People'. 

Telling your supposedly smart stroke medical 'professionals' they know nothing about stroke is a no-no even if it is true. 

Politeness will never solve anything in stroke. Yes, I'm a bomb thrower and proud of it. Someday a stroke 'leader' will try to ream me out for making them look bad by being truthful, I look forward to that day.

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

Authors Andrgie AT , Liao CH, Wu TY, Yang HH, Harn HJ, Lin SZ , Chen YS , Tsai HC

Received 5 December 2024

Accepted for publication 15 April 2025

Published 7 May 2025 Volume 2025:20 Pages 5893—5905

DOI https://doi.org/10.2147/IJN.S507362

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Prof. Dr. RDK Misra

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Abegaz Tizazu Andrgie,¹ Cheng-Han Liao,² Tsung-Yun Wu,^2,3 Hsueh-Hui Yang,⁴ Horng-Jyh Harn,^5,6 Shinn-Zong Lin,^5,7 Yu-Shuan Chen,^4,5,8 Hsieh-Chih Tsai<sup>2,3,9

1</sup>Department of Biotechnology, Debre Berhan University, Debre Berhan, Ethiopia; ²Graduate Institute of Applied Science and Technology, National Taiwan University of Science and Technology, Taipei, 106, Taiwan, Republic of China; ³Advanced Membrane Materials Center, National Taiwan University of Science and Technology, Taipei, 106, Taiwan; ⁴Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; ⁵Bioinnovation Center, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; ⁶Department of Pathology, Hualien Tzu Chi Hospital, Tzu Chi University, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; ⁷Department of Neurosurgery, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970, Taiwan; ⁸Center for General Education, Tzu Chi University, Hualien, 970, Taiwan; ⁹R&D Center for Membrane Technology, Chung Yuan Christian University, Taoyuan, 320, Taiwan

Correspondence: Yu-Shuan Chen, Email yushuanchenxie@gmail.com Hsieh-Chih Tsai, Email h.c.tsai@mail.ntust.edu.tw

Introduction: 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.
Methods: 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.
Results: 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.
Conclusion: 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.

Keywords: blood-brain barrier, DiR labeling, permeability, sustained release, nanogels

Introduction

Numerous brain diseases have poor prognoses and low survival rates, with limited diagnostic and therapeutic options owing to the presence of the blood-brain barrier (BBB). The BBB regulates the exchange of substances between the circulatory system and brain, limiting the access of drugs to the brain parenchyma.^1–3 Surgical techniques are commonly used to overcome the limitations associated with the BBB and circumvent this natural biological barrier.⁴ However, these invasive approaches present a risks, including nerve damage and local inflammatory reactions. Recent research has focused on developing minimally invasive approach to deliver therapeutics through the BBB to brain tissues.^5,6 Among these, injectable thermosensitive hydrogels have gained attention as promising carriers owing to their unique properties of existing as free-flowing fluids at room temperature and converting into viscous gels at body temperature. Owing to their unique properties for minimally invasive administration, hydrogels in their liquid state can be administered anywhere behind biological barriers using a small needle, eliminating the need for invasive surgery.^7–10 The In situ gel-forming materials form a depot for the sustained release of therapeutic agents.

In particular, in situ gel-forming thermosensitive nanogel systems have emerged as promising nanocarriers for therapeutic delivery. With advancements in nanotechnology, nanocarriers offer a promising solution owing to their small size, high surface-to-volume ratios, and tunable multifunctional properties, enabling injectable structures to penetrate physiological barriers.¹¹ The most interesting characteristics of nanocarriers as drug delivery systems are their high loading capacity, long-term stability, and responsiveness to different stimuli, leading to increased drug concentration in target tissues by prolonging drug diffusion time and increasing the possibility of drug penetration through physiological barriers.¹²

Thermoresponsive injectable nanogels composed of polymers can form gels in situ in response to various stimuli. Among the various thermoresponsive polymers, Pluronic F127 (PF 127) is a synthetic polymer that has been extensively investigated as an injectable nanogel for drug delivery applications.^13–16 PF 127 is an amphiphilic triblock copolymer composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(propylene oxide) (PPO).¹⁷ Owing to its amphiphilic properties, PF127 can self-assemble into small micelle structures in aqueous solutions and undergo a sol-gel phase transition with increasing environmental temperature.¹⁸ At low temperatures, the PPO blocks exhibit weak hydrophobicity, and with increasing temperature, the PEO groups become dehydrated and aggregate to form micelles.^8,19 The gelation temperature of PF127 can be controlled by adjusting the individual concentrations of the polymer blocks or by chemically modifying PF127 to increase its mechanical performance. This is because the native PF127 hydrogels exhibit low mechanical strength and stability despite their thermosensitive properties,²⁰ posing challenges in brain-targeting studies because the hydrogel might degrade too rapidly to effectively reach the brain. To address this issue, native and terminal-functionalized PF127 have been investigated for improved performance in brain-targeting applications. Modified PF127 polymers exhibit good mechanical properties as hydrogels and can encapsulate hydrophobic drugs in the hydrophobic core, providing stability and protection from external conditions.

In this study, the PF127 polymer was chemically modified using β-alanine (ADF127) and ethylenediamine (EDF127) for crosslinking the polymer chain through highly directed and intense hydrogen bonding interactions to improve the mechanical properties of the hydrogel. The intermolecular hydrogen bonding between the carboxyl and amine groups of β-alanine (ADF127) and ethylenediamine (EDF127) provides sufficient mechanical properties for the material to behave as a controlled drug carrier or to enable the sustained release of 3-butylidenephthalide (BP), an anticancer drug. The mechanical properties and thermo-response behavior of the copolymers were investigated using a rheometer in the dynamic oscillation mode, as reported in our previous work.²¹ Structural observations using scanning electron microscopy and the investigation of drug release and drug entrapment efficiency allowed the evaluation of the mechanical structure and stability of the modified nanogels. The in vivo biodistribution patterns of the DiR-loaded copolymeric hydrogels were investigated in a mouse model after intravenous injection using an in vivo imaging system (IVIS). This study further investigated the use of DiR-loaded EDF127 and ADF127 copolymeric nanogels to quantify and visualize their biodistribution in the brain tissue.

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