Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy.
Acta Pharm Sin B
; 9(2): 397-409, 2019 Mar.
Article
en En
| MEDLINE
| ID: mdl-30972285
Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.
AD-B-PEG, the pH-responsive adamantane-PEG conjugate; AD-O-PEG, the non-pH sensitive adamantane-PEG conjugate; ADA, 1-adamantane carboxylic acid; AUC, area under the plasma concentrationtime curve; Active-targeting; Benzoic imine linkage; CLSM, confocal laser scanning microscope; Cancer therapy; DAPI, 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride; DCC, N,N'-dicyclohexylcarbodiimide; DCM, dichloromethane; DDS, drug delivery systems; DL, drug-loading content; DLS, dynamic light scattering; DMAP, 4-dimethylaminopyrideine; DMEM, Dulbecco׳s modified Eagle׳s medium; DiR, 1,1'-dioctadecyltetramethyl indotricarbocyanine iodide; Dox/HCVBP, Dox-loaded hyaluronic acid-based transformable supramolecular nanoplatform; Dox/HCVOP, Dox-loaded hyaluronic acid-based untransformable supramolecular nanoplatform; Dox·HCl, doxorubicin hydrochloride; EDC, 1-ethyl-3-(3-dimethyalminopropl) carbodiimide; EE, encapsulation efficiency; FBS, fetal bovine serum; H&E, hematoxylin and eosin; HA, hyaluronic acid; HA-CD, hydroxypropyl-ß-cyclodextrin grafted hyaluronic acid polymer; HCBP, hydroxypropyl-ß-cyclodextrin grafted hyaluronic acid polymer and pH-responsive adamantane-PEG conjugate inclusion complex; HCPs, hydroxypropyl-ß-cyclodextrin grafted hyaluronic acid polymer and adamantane-PEG conjugate inclusion complexes; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesul-fonic acid; HOBT, 1-hydroxybenzotriazole; HPCD, hydroxypropyl-ß-cyclodextrin; Hyaluronic acid; MW, molecular weight; NPs, nanoparticles; Natural ligand; PCC, Pearson׳s correlation coefficient; PDI, polydispersity index; PEG dilemma; RES, reticuloendothelial system; RPMI-1640, Roswell Park Memorial Institute-1640; Supramolecular nanoplat-form; THF, tetrahydrofuran; TUNEL, terminal deoxynucleotidyl transferased dUTP nick end labeling; Transformative nanoparti-cles; VES, vitamin E succinate; pHe, the extracellular pH
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Idioma:
En
Revista:
Acta Pharm Sin B
Año:
2019
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos