Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy.
10.1016/j.apsb.2018.11.006
- Author:
Lu ZHONG
1
;
Lu XU
1
;
Yanying LIU
1
;
Qingsong LI
1
;
Dongyang ZHAO
1
;
Zhenbao LI
1
;
Huicong ZHANG
1
;
Haotian ZHANG
2
;
Qiming KAN
2
;
Yongjun WANG
1
;
Jin SUN
1
;
Zhonggui HE
1
Author Information
1. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. Department of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
- Publication Type:Journal Article
- Keywords:
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 concentration—time 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-β-cyclodextrin grafted hyaluronic acid polymer;
HCBP, hydroxypropyl-β-cyclodextrin grafted hyaluronic acid polymer and pH-responsive adamantane-PEG conjugate inclusion complex;
HCPs, hydroxypropyl-β-cyclodextrin grafted hyaluronic acid polymer and adamantane-PEG conjugate inclusion complexes;
HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesul-fonic acid;
HOBT, 1-hydroxybenzotriazole;
HPCD, hydroxypropyl-β-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
- From:
Acta Pharmaceutica Sinica B
2019;9(2):397-409
- CountryChina
- Language:English
-
Abstract:
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 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 and 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 nonspecific biodistribution.
