Tumor microenvironment dual-responsive core–shell nanoparticles with hyaluronic acid-shield for efficient co-delivery of doxorubicin and plasmid DNA

Abstract

As the tumor microenvironment (TME) develops, it is critical to take the alterations of pH value, reduction and various enzymes of the TME into consideration when constructing the desirable co-delivery systems. Herein, TME pH and enzyme dual-responsive core–shell nanoparticles were prepared for the efficient co-delivery of chemotherapy drug and plasmid DNA (pDNA). A novel pH-responsive, positively charged drug loading material, doxorubicin (DOX)-4-hydrazinobenzoic acid (HBA)-polyethyleneimine (PEI) conjugate (DOX-HBA-PEI, DHP), was synthesized to fabricate positively charged polyion complex inner core DHP/DNA nanoparticles (DDN). Hyaluronic acid (HA) was an enzyme-responsive shell which could protect the core and enhance the co-delivery efficiency through CD44-mediated endocytosis. The HA-shielded pH and enzyme dual-responsive nanoparticles (HDDN) were spherical with narrow distribution. The particle size of HDDN was 148.3±3.88 nm and the zeta potential was changed to negative (−18.1±2.03 mV), which led to decreased cytotoxicity. The cumulative release of DOX from DHP at pH 5.0 (66.4%) was higher than that at pH 7.4 (30.1%), which indicated the pH sensitivity of DHP. The transfection efficiency of HDDN in 10% serum was equal to that in the absence of serum, while the transfection of DDN was significantly decreased in the presence of 10% serum. Furthermore, cellular uptake studies and co-localization assay showed that HDDN were internalized effectively through CD44-mediated endocytosis in the tumor cells. The efficient co-delivery of DOX and pEGFP was confirmed by fluorescent image taken by laser confocal microscope. It can be concluded that TME dual-responsive HA-shielded core–shell nanoparticles could be considered as a promising platform for the co-delivery of chemotherapy drug and pDNA.

Co-delivery of sorafenib and VEGF-siRNA via pH-sensitive liposomes for the synergistic treatment of hepatocellular carcinoma

“…During the recent past, there has been a remarkable progress in constructing drug/siRNA co-loaded delivery systems. The representative candidates, including liposomes/lipid nanoparticles [8], cationic polymer/micelle [9], and inorganic nanoparticles [10], have been extensively studied and discussed. Among these nanocarriers, cationic liposomes are one of the most successful co-loaded systems: (1) low toxicity and ease of preparation; (2) the ability of loading hydrophobic, amphipathic, and hydrophilic drugs; (3) forming positively lipoplex with siRNA and facilitating cellular uptake; (4) aiding in endosomal escape of siRNA [11,12].…”

Quercetin and doxorubicin co-delivery using mesoporous silica nanoparticles enhance the efficacy of gastric carcinoma chemotherapy

“…36,37 As a result, DOX is often used together with other agents to further improve its anticancer performance as well as reduce the side effects. 38,39 Co-delivering systems have been widely explored by precious works, in which polymer-based DDS, such as HA, 40 polyethylene glycol, 4 chondroitin sulfate, 36 etc have shown great promise in overcoming the abovementioned dilemma. However, compared with previous works' focus on co-delivering QC and DOX, 41,42 persistent work is still required on the fabrication of a reliable and reproducible hybrid platform with decent drug-loading capability as well as tumor targetability to enhance the co-delivering efficacy in GC chemotherapy.…”

Hyaluronic Acid-Conjugated with Hyperbranched Chlorin e6 Using Disulfide Linkage and Its Nanophotosensitizer for Enhanced Photodynamic Therapy of Cancer Cells

“…Lee and Jeong approved that the fluorescence intensity of Ce6 was increased by the degradation of disulfide bond in the nanoparticles and then the release of anticancer drug was accelerated [30]. Furthermore, the CD44 receptor is normally over-expressed in the aggressive cancer cells, such as U87MG cells or HCT116 cells, and closely associated with motility on the HA-coated surface [26,53]. These properties can also be applicable in tumor targeting while using HA-bioactive agent conjugates [26,29,54].…”

“…The biochemical and pathophysiological characters of microenvironment of tumor tissues are quite different to normal counterpart [24]. The tumor cells are characterized by a higher expression of receptors, higher enzymatic activity, such as hyaluronidase (HAse), poor perfusion, acidic pH environment, and higher reduction/oxidation (redox) status when compared to normal cells [24,25,26]. Subsequently, the tumor microenvironment has quite different physiological states as compared to normal tissues.…”

“…CD44 receptor is related to the growth, migration, and metastasis of cancer cells [27]. Many scientists have investigated HA as a targeting moiety of nanomedicine for long decades [26,28,29,30]. Lee and Jeong reported that the nanoparticles of HA-Ce6-poly(L-histidine) conjugates specifically deliver the anticancer drug to a CD44 receptor of MDA-MB 231 cells at in vitro and in vivo [30].…”