Boronic acid-tethered amphiphilic hyaluronic acid derivative-based nanoassemblies for tumor targeting and penetration.

Abstract

(3-Aminomethylphenyl)boronic acid (AMPB)-installed hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated for tumor-targeted delivery. The amine group of AMPB was conjugated to the carboxylic acid group of hyaluronic acid (HA) via amide bond formation, and synthesis was confirmed by spectroscopic methods. HACE-AMPB/MB NPs with a 239-nm mean diameter, narrow size distribution, negative zeta potential, and >90% drug encapsulation efficiency were fabricated. Exposed AMPB in the outer surface of HACE-AMPB NPs (in the aqueous environment) may react with sialic acid of cancer cells. The improved cellular accumulation efficiency, in vitro antitumor efficacy, and tumor penetration efficiency of HACE-AMPB/MB NPs, compared with HACE/MB NPs, in MDA-MB-231 cells (CD44 receptor-positive human breast adenocarcinoma cells) may be based on the CD44 receptor-mediated endocytosis and phenylboronic acid-sialic acid interaction. Enhanced in vivo tumor targetability, infiltration efficiency, and antitumor efficacies of HACE-AMPB NPs, compared with HACE NPs, were observed in a MDA-MB-231 tumor-xenografted mouse model. In addition to passive tumor targeting (based on an enhanced permeability and retention effect) and active tumor targeting (interaction between HA and CD44 receptor), the phenylboronic acid-sialic acid interaction can play important roles in augmented tumor targeting and penetration of HACE-AMPB NPs. STATEMENT OF SIGNIFICANCE: (3-Aminomethylphenyl)boronic acid (AMPB)-tethered hyaluronic acid-ceramide (HACE)-based nanoparticles (NPs), including manassantin B (MB), were fabricated and their tumor targeting and penetration efficiencies were assessed in MDA-MB-231 (CD44 receptor-positive human adenocarcinoma) tumor models. MB, which exhibited antitumor efficacies via the inhibition of angiogenesis and hypoxia inducible factor (HIF)-1, was entrapped in HACE-AMPB NPs in this study. Phenylboronic acid located in the outer surface of HACE-AMPB/MB NPs (in the aqueous milieu) may react with the sialic acid over-expressed in cancer cells and intramolecular B‒O bond can be formed. This phenylboronic acid-sialic acid interaction may provide additional tumor targeting and penetration potentials together with an enhanced permeability and retention (EPR) effect (passive tumor targeting) and HA-CD44 receptor interaction (active tumor targeting). Developed HACE-AMPB NP may be one of promising nanocarriers for the imaging and therapy of CD44 receptor-expressed cancers.

• Authors: Jae Young Jeong, Eun-Hye Hong, Song Yi Lee, Jae-Young Lee, Jae-Hyoung Song, Seung-Hak Ko, Jae-Seong Shim, Sunghwa Choe, Dae-Duk Kim, Hyun-Jeong Ko, Hyun-Jong Cho
• Journal: Acta biomaterialia (Acta Biomater) Vol. 53 Pg. 414-426 (04 15 2017) ISSN: 1878-7568 [Electronic] England
• PMID: 28216300 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Boronic Acids
• Ceramides
• Cross-Linking Reagents
• Nanocapsules
• Nanoconjugates
• Hyaluronic Acid

Topics

• Boronic Acids (chemistry)
• Cell Line, Tumor
• Ceramides (chemistry)
• Cross-Linking Reagents (chemistry)
• Diffusion
• Humans
• Hyaluronic Acid (chemistry)
• Hydrophobic and Hydrophilic Interactions
• Nanocapsules (chemistry, ultrastructure)
• Nanoconjugates (chemistry, ultrastructure)
• Neoplasms, Experimental (chemistry, pathology)
• Particle Size