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- 2019
Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapyDOI: 10.1016/j.apsb.2018.11.006 Keywords: ADA, 1-adamantane carboxylic acid, AD-B-PEG, the pH-responsive adamantane-PEG conjugate, AD-O-PEG, the non-pH sensitive adamantane-PEG conjugate, AUC, area under the plasma concentration—time curve, CLSM, confocal laser scanning microscope, DAPI, 2-(4-amidinophenyl)-6-indolecarbamidine dihydrochloride, DCC, N,N′-dicyclohexylcarbodiimide, DCM, dichloromethane, DDS, drug delivery systems, DiR, 1,1′-dioctadecyltetramethyl indotricarbocyanine iodide, DL, drug-loading content, DLS, dynamic light scattering, DMAP, 4-dimethylaminopyrideine, DMEM, Dulbecco？s modified Eagle？s medium, Dox·HCl, doxorubicin hydrochloride, Dox/HCVBP, Dox-loaded hyaluronic acid-based transformable supramolecular nanoplatform, Dox/HCVOP, Dox-loaded hyaluronic acid-based untransformable supramolecular nanoplatform, EDC, 1-ethyl-3-(3-dimethyalminopropl) carbodiimide, EE, encapsulation efficiency, FBS, fetal bovine serum, 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, H&E, hematoxylin and eosin, HOBT, 1-hydroxybenzotriazole, HPCD, hydroxypropyl-β-cyclodextrin, MW, molecular weight, NPs, nanoparticles, PCC, Pearson？s correlation coefficient, PDI, polydispersity index, pHe, the extracellular pH, RES, reticuloendothelial system, RPMI-1640, Roswell Park Memorial Institute-1640, THF, tetrahydrofuran, TUNEL, terminal deoxynucleotidyl transferased dUTP nick end labeling, VES, vitamin E succinate Hyaluronic acid, Benzoic imine linkage, Active-targeting, Cancer therapy, Natural ligand, Supramolecular nanoplat-form, Transformative nanoparti-cles, PEG dilemma 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 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
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