Although aptamers are well-known as cell-specific membrane biomarkers for tumor-targeted therapy, it is important to avoid their degradation by nucleases in vivo. In this study, we developed a MUC1 aptamer–doxorubicin nanoconjugate (APT-DOX) through an acid-labile linkage and embedded APT-DOX into a thermosensitive hydrogel for antitumor therapy. The hydrogels exhibit a sol–gel transition upon intratumoral injection, resulting in the protection and controlled release control of APT-DOX with the shielding of the gel network. Moreover, the released APT-DOX was prone to be enriched at the tumor cells due to specific intracellular transport by the overexpressing MUC1 protein; however, APT-DOX regained the free DOX form via the rupture of the linkage under tumor cells lysosome acidic conditions and achieved increased concentration in the nucleus for antitumor treatment.

Currently, polysaccharide-based hydrogels are widely studied macromolecular networks to modify drug dissolution from controlled-releasing matrix tablets. Among them, polyelectrolyte complexes (PEC) films consisted of chitosan (CS) and sodium alginate (SA) could be obtained via spontaneously assembling under physiological gastrointestinal environment. Here, we utilized these self-assembled PEC films as an efficient coating materials to develop controlled-released matrix tablets through compression coating process, with paracetamol (APAP) as model drug. The constitutive and morphology characteristic studies on these PEC films illustrated that the mixture of CS and SA with the weight ratio of 1:1 would be an promising outer layer for compression-coating tablets. In addition, the in vitro drug releasing behavior experiments demonstrated that the optimized compression coating tablets displayed satisfied zero-order drug releasing profits. Furthermore, the in vivo pharmacokinetic studies of these APAP loaded compression-coated tablets in New Zealand rabbits gave that the Tmax (12.32 ± 1.05 h) was significantly prolonged (p < 0.01), compared to that (0.89 ± 0.26 h) of common APAP tablets (Jinfuning®) after oral administration. These studies suggest that the compression-coated tablets with self-assembled PEC film as coating outer layer may be a promising strategy for peroral controlled release delivery system of water soluble drugs.Open image in new window

Currently, polysaccharide-based hydrogels are widely studied macromolecular networks to modify drug dissolution from controlled-releasing matrix tablets. Among them, polyelectrolyte complexes (PEC) films consisted of chitosan (CS) and sodium alginate (SA) could be obtained via spontaneously assembling under physiological gastrointestinal environment. Here, we utilized these self-assembled PEC films as an efficient coating materials to develop controlled-released matrix tablets through compression coating process, with paracetamol (APAP) as model drug. The constitutive and morphology characteristic studies on these PEC films illustrated that the mixture of CS and SA with the weight ratio of 1:1 would be an promising outer layer for compression-coating tablets. In addition, the in vitro drug releasing behavior experiments demonstrated that the optimized compression coating tablets displayed satisfied zero-order drug releasing profits. Furthermore, the in vivo pharmacokinetic studies of these APAP loaded compression-coated tablets in New Zealand rabbits gave that the Tmax (12.32 ± 1.05 h) was significantly prolonged (p < 0.01), compared to that (0.89 ± 0.26 h) of common APAP tablets (Jinfuning®) after oral administration. These studies suggest that the compression-coated tablets with self-assembled PEC film as coating outer layer may be a promising strategy for peroral controlled release delivery system of water soluble drugs.Open image in new window

Most nanoparticles (NPs) have difficulty deeply penetrating into tumor tissues. Here, we designed a spatially controlled multistage nanocarrier by encapsulating small polyamidoamine (PAMAM) dendrimers (~5 nm) within large gelatin NPs (~200 nm). This multistage nanocarrier is meant to be stable during systemic circulation and to leak through tumor vasculature walls by the enhanced permeation and retention (EPR) effect. Afterwards, this multistage nanocarrier release PAMAM dendrimers in response to the high matrix metalloproteinase-2 (MMP-2) enzymes in the tumor microenvironment, and further transport into tumor cells. In this study, the demonstrated high intracellular uptake and deep penetration into tumor model verified the effective enzymes-responsively and spatially controlled multistage penetration of these combined nanocarriers. In addition, these multistage nanocarrier were further loaded with anti-tumor drug methotrexate (MTX) and evaluated both in vitro and in vivo to investigate their anti-tumor effect, which demonstrated that this multistage nanocarrier hold great potential in improving anti-tumor efficiency.A spatially controlled multistage nanocarrier with small polyamidoamine (PAMAM) dendrimers (~5 nm) encapsulating into large gelatin NPs (~200 nm). With an outer gelatin layer to act as a shield, these multistage nanocarriers were more stable during systematic circulation for their relatively large particle size and electrically neutral surface, than positively charged PAMAM dendrimers alone. However, gelatin NPs were degraded via matrix metalloproteinase-2 (MMP-2) enzymes in tumor tissue, triggering an internal release of PAMAM dendrimers that possessed small particle sizes and a positive charge, which guaranteed improved subsequent deep penetration and high intracellular uptake into tumor cells through electrostatic adsorptive endocytosis.Download high-res image (364KB)Download full-size image

•Multi-scale HA nanoparticles encapsulated with PAMAM dendrimers were developed.•The fine bio-stimuli-responsive properties of HA/PAMAM nanoparticles was verified.•The in vitro tumor spheroids deeply penetration of HA/PAMAM-FITC was confirmed.•HA/PAMAM-FITC showed prolonged systematic circulation in mice bearing H22 tumor.•HA/PAMAM-MTX demonstrated higher antitumor activity in H22 sarcoma mice.In this study, we developed bio-stimuli-responsive multi-scale hyaluronic acid (HA) nanoparticles encapsulated with polyamidoamine (PAMAM) dendrimers as the subunits. These HA/PAMAM nanoparticles of large scale (197.10 ± 3.00 nm) were stable during systematic circulation then enriched at the tumor sites; however, they were prone to be degraded by the high expressed hyaluronidase (HAase) to release inner PAMAM dendrimers and regained a small scale (5.77 ± 0.25 nm) with positive charge. After employing tumor spheroids penetration assay on A549 3D tumor spheroids for 8 h, the fluorescein isothiocyanate (FITC) labeled multi-scale HA/PAMAM-FITC nanoparticles could penetrate deeply into these tumor spheroids with the degradation of HAase. Moreover, small animal imaging technology in male nude mice bearing H22 tumor showed HA/PAMAM-FITC nanoparticles possess higher prolonged systematic circulation compared with both PAMAM-FITC nanoparticles and free FITC. In addition, after intravenous administration in mice bearing H22 tumors, methotrexate (MTX) loaded multi-scale HA/PAMAM-MTX nanoparticles exhibited a 2.68-fold greater antitumor activity.

•Chitosan hydrogel was modified by polyvinyl alcohol and glutaraldehyde.•The modified CS hydrogel showed a fine thermosensitive property.•The mechanical strength of the modified CS hydrogel was highly improved.•PTX loaded modified hydrogel showed a sustained drug release profile.•Superior anti-tumor efficiency of PTX-loaded modified hydrogels was verified.Thermosensitive in situ hydrogels are potential candidates to achieve intratumoral administration, nevertheless their weak mechanical strength always lead to serious drug leakage and burst. Herein, we developed a chitosan based thermosensitive hydrogel of high mechanical strength, which was modified by glutaraldehyde (GA) and polyvinyl alcohol (PVA), for intratumoral delivery of paclitaxel (PTX). The modified hydrogel system could achieve sol–gel transition at 35.79 ± 0.4 °C and exhibit a 7.03-fold greater mechanical strength compared with simple chitosan hydrogel. Moreover, the drug release of PTX loaded modified hydrogel in PBS (pH 7.4) was found to be extended to 13 days. After intratumoral administration in mice bearing H22 tumors, PTX-loaded modified hydrogels exhibited a 3.72-fold greater antitumor activity compared with Taxol®. Overall, these modified hydrogel systems demonstrated to be a promising way to achieve efficient sustained release and enhanced anti-tumor therapy efficiency of anticancer drugs through in situ tumor injectable administration.

•HA was successfully conjugated with PAMAM dendrimers, and TPT was loaded.•The modification of HA significantly reduced the cytotoxicity of PAMAM.•The fine in vitro and in vivo targeting efficiency of HA-PAMAM/TPT was confirmed.•HA-PAMAM/TPT showed prolonged circulation in normal rats, similar to pegylation.•HA-PAMAM/TPT demonstrated higher antitumor activity in S-180 sarcoma mice.Herein, we developed dualfunctional hyaluronic acid (HA)-grafted polyamidoamine (PAMAM) dendrimers for simultaneous systemic long circulation and active tumor targeting and delivery of topotecan hydrochloride (TPT). The possibility of these modified dendrimers as nanocarriers for promoting tissue distribution and antitumor efficiency, as well as a drug release profile, cytotoxicity and cellular uptake, was investigated. The fine targeting efficiency of HA-PAMAM/TPT was confirmed by the CD44 receptor-mediated high cellular uptake efficiency and low cytotoxicity in HCT-116 cells, and the in vivo higher tumor distribution percentage than in other tissues in mice bearing an S-180 tumor. Pharmacokinetic studies showed that the t1/2 and MRT of TPT were significantly extended after intravenous administration of HA-PAMAM/TPT in normal rats. Moreover, TPT-loaded nanovehicles demonstrated higher antitumor activity compared with free drug and PAMAM/TPT. Overall, HA-PAMAM may be an alternative vector for the effective targeted delivery of and tumor therapy with antitumor drugs.

The aims of this study were to prepare fine intra-articular–administrated chitosan thermosensitive hydrogels combined with alginate microspheres and to investigate the possibility of those hydrogels as a drug delivery system for promoting the anti-inflammation effect. Diclofenac sodium containing alginate microspheres was prepared by a modified emulsification and/or gelation method and then dispersed into injectable thermosensitive hydrogels, consisting of chitosan and β-glycerophosphate. The final combined hydrogels were evaluated in terms of their morphology properties, rheological properties, in vitro drug release, and in vivo biocompatibility and pharmacodynamics behaviors. The optimized formulation exhibited sol-gel transition at 31.72 ± 0.42°C and quickly turned into gel within 5 min, with sustained drug release characteristics followed Ritger-Peppas equation, which could prolong the in vitro drug release to 5 days. In addition, the anti-inflammation efficacy of the combined hydrogels in rabbits with experimental rheumatoid arthritis was higher than that of drug solution and pure chitosan hydrogels. Those results demonstrated that these combined hydrogels could become a potential drug delivery system for improving the therapeutic effect of diclofenac sodium and suggested an important technology platform for intra-articular administration.