title: 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.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
authors.forename: Jae Young
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
authors.forename: Song Yi
authors.initials: SY
authors.lastname: Lee
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea.
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Song
authors.affiliation: Biogenics Inc., Daejeon 34027, Republic of Korea.
authors.forename: Seung-Hak
authors.initials: SH
authors.lastname: Ko
authors.affiliation: Biogenics Inc., Daejeon 34027, Republic of Korea; Skin & Tech Inc., Seongnam, Gyeonggi 13135, Republic of Korea.
authors.forename: Jae-Seong
authors.initials: JS
authors.lastname: Shim
authors.affiliation: Convergence Research Center for Functional Plant Products, Advanced Institutes of Convergence Technology, Suwon, Gyeonggi 16229, Republic of Korea.
authors.forename: Sunghwa
authors.initials: S
authors.lastname: Choe
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Dae-Duk
authors.initials: DD
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea; Convergence Research Center for Functional Plant Products, Advanced Institutes of Convergence Technology, Suwon, Gyeonggi 16229, Republic of Korea. Electronic address: hjko@kangwon.ac.kr.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea. Electronic address: hjcho@kangwon.ac.kr.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
mesh_terms: D001897:Boronic Acids / Q000737:chemistry*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D004058:Diffusion; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D053769:Nanocapsules / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D009374:Neoplasms, Experimental / Q000737:chemistry* / Q000473:pathology; D010316:Particle Size
chemical_list: D001897:Boronic Acids; D002518:Ceramides; D003432:Cross-Linking Reagents; D053769:Nanocapsules; D058726:Nanoconjugates; D006820:Hyaluronic Acid
keywords: Hyaluronic acid-ceramide; Nanoparticle; Phenylboronic acid; Tumor penetration; Tumor targeting