Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

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.

High-drug-loading capacity of redox-activated biodegradable nanoplatform for active targeted delivery of chemotherapeutic drugs

Challenges associated with low-drug-loading capacity,lack of active targeting of tumor cells and unspecific drug release of nanocarriers synchronously plague the success of cancer therapy.Herein,we constructed active-targeting,redox-activated polymeric micelles(HPGssML)selfassembled aptamer-decorated,amphiphilic biodegradable poly(benzyl malolactonate-co-e-caprolactone)copolymer with disulfide linkage and p-conjugated moieties.HPGssML with a homogenous spherical shape and nanosized diameter(-150 nm)formed a low critical micellar concentration(10^-3mg/mL),suggesting good stability of polymeric micelles.The anticancer drug,doxorubicin(DOX),can be efficiently loaded into the core of micelles with high-drug-loading content via strong π-π interaction,which was verified by a decrease in fluorescence intensity and redshift in UV adsorption of DOX in micelles.The redox sensitivity of polymeric micelles was confirmed by size change and in vitro drug release in a reducing environment.Confocal microscopy and flow cytometry assay demonstrated that conjugating aptamers could enhance specific uptake of HPGssML by cancer cells.An in vitro cytotoxicity study showed that the half-maximal inhibitory concentration(IC50)of DOX-loaded HPGssML was two times lower than that of the control group,demonstrating improved antitumor efficacy.Therefore,the multifunctional biodegradable polymeric micelles can be exploited as a desirable drug carrier for effective cancer treatment.