Sorafenib-Loaded PLGA-TPGS Nanosystems Enhance Hepatocellular Carcinoma Therapy Through Reversing P-Glycoprotein-Mediated Multidrug Resistance.

Multidrug resistance (MDR) is a key determinant for hepatocellular carcinoma chemotherapy failure. P-glycoprotein is one of the main causes of MDR by causing drug efflux in tumor cells. In order to solve this thorny problem, we prepared a sorafenib-loaded polylactic acid-glycolic acid (PLGA) - D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) nanoparticles (SPTNs). SPTNs were successfully synthesized through an ultrasonic emulsion solvent evaporation method with a favourable encapsulation efficiency of 90.35%. SPTNs were almost spherical in shape with uniform particle size (215.70 ± 0.36 nm), narrow polydispersity index (0.27 ± 0.02) and negative surface charge (-26.01 ± 0.65 mV). In the cellular uptake assay, the intracellular coumarin-6 (C6) fluorescence of TPGS component-based PLGA nanoparticles (C6-PTNs) was 1.63-fold higher relative to that of PVA component-based PLGA nanoparticles (C6-PVNs). The half-maximal inhibitory concentration and apoptosis ratio of SPTNs against HepG2/MDR cells were 3.90 µM and 75.62%, respectively, which were notably higher than free SF and sorafenib-PLGA-PVA nanoparticles (SPVNs). The anti-drug efflux activities of SPTNs were assessed by the intracellular trafficking assay using verapamil as a P-gp inhibitor. SPTNs could effectively inhibit the drug efflux in tumor cells detected by flow cytometry, and suppressed relative MDR1 gene as well as P-glycoprotein expression in tumor cells. Attributed to the MDR reversion effect of SPTNs, the in vivo antitumor efficacy experiment showed that SPTNs significantly inhibited the tumor growth of HepG2/MDR xenograft-bearing nude mice, and obviously reduced the toxicity against liver and kidney compared with SF treatment. In summary, SPTNs, as highly efficient and safe antitumor nano delivery systems, showed promising potential for hepatocellular carcinoma therapy through reversing P-glycoprotein-mediated MDR. Graphical Abstract.

Pueraria flavones-loaded bile salt liposomes with improved intestinal absorption and oral bioavailability: in vitro and in vivo evaluation.

Pueraria flavone (PF), the main component of Pueraria lobata, is a traditional Chinese medicine used for the treatment of cardiovascular and cerebrovascular diseases; however, it exhibits low oral bioavailability because of its poor membrane permeability. In this study, PF-loaded sodium deoxycholate-decorated liposomes (SDC-Lips) were prepared using the reverse-phase evaporation method and optimised using the Box-Behnken design method. The morphology, particle size, zeta potential, and entrapment efficiency of these PF-loaded SDC-Lips were evaluated. The release behaviours of PF-loaded SDC-Lips in simulated gastric and intestinal fluids were consistent with the Weibull kinetic model. In situ intestinal perfusion studies showed that the absorption characteristics of free PF in rats were mainly passive diffusion and partly active transport, and the duodenum was the main absorption site. After encapsulated with SDC-Lips, the absorption of PF increased significantly. The in vivo pharmacokinetic parameters of area under the plasma concentration-time curve (AUC)(0 → 12 h) and AUC(0 → ∞) of PF-loaded SDC-Lips after intragastric administration were 1.34-fold and 1.543-fold, respectively. Overall, the PF-loaded SDC-Lips improved the oral absorption of PF by increasing its solubility and might be considered a promising formulation strategy for prolonging the biological activity time of PF.

Facile nose-to-brain delivery of rotigotine-loaded polymer micelles thermosensitive hydrogels: In vitro characterization and in vivo behavior study.

A rotigotine (ROT)-loaded polymer micelles thermosensitive gel (ROT-PM-TSG) delivery system was engineered to enhance the solubility of the drug, prolong the residence time, and increase the concentration of the drug in the brain tissue. First, ROT-loaded polymer micelles (ROT-PM) were tailored and optimized. The average particle size, encapsulation efficiency, and drug loading of the ROT-PM were (88.62 ± 1.47) nm, (93.5 ± 0.79) %, and (19.9 ± 0.60) %. The optimal ROT-PM-TSG formulation contained 22% P407 and 2% P188 with a gelation temperature of about 32.3 °C and a pH of 5.186. In vivo, the MRT of ROT-PM and ROT-PM-TSG nasal administration was 1.43 and 1.79 times extended than that of the intravenous. In comparison with the intravenous group, the distribution of ROT in olfactory bulb, cerebrum, cerebellum and striatum was 276.6%, 170.5%, 166.5% and 184.4%, respectively. In conclusion, the ROT-PM-TSG system has proven to be a potential application prospect as a ROT nose-to-brain delivery system.

Polyvinylpyrrolidone microneedles for localized delivery of sinomenine hydrochloride: preparation, release behavior of in vitro & in vivo, and penetration mechanism.

Sinomenine (SIN) is an anti-inflammatory alkaloid derived from Sinomenium acutum, and the products sinomenine hydrochloride (SH) tablets and injections have been marketed in China to treat rheumatoid arthritis (RA). Oral administration of SH has shortcomings of gastrointestinal irritation and low bioavailability. The injection may require professional training and higher cost. It is of interest to develop an alternative form that is easier to administer and avoids the first-pass metabolism. In this study, SH-loaded dissolving microneedles (SH-MN) were fabricated using polyvinyl pyrrolidone and chondroitin sulfate with a casting method. In percutaneous permeation studies of In vitro, the cumulative permeation and permeation rate of SH-MN were 5.31 and 5.06 times higher than that of SH-gel (SH-G). In percutaneous pharmacokinetic studies, the values of the area under the curve after administration of SH-MN in the skin and blood were 1.43- and 1.63-fold higher than that of SH-G, respectively. In percutaneous absorption studies, SH-MN could absorb into tissue fluid; and dissolve after skin penetration. The drug was released along the channel and spread to surrounding skin tissue. After 4 h, the needle tip was almost completely dissolved, and the drug could penetrate to a depth of 200 µm under the skin. These results demonstrate that the SH-MN is an effective, safe, and simple strategy for transdermal SH delivery.

In situ low-immunogenic albumin-conjugating-corona guiding nanoparticles for tumor-targeting chemotherapy.

Nanoparticles (NPs) are unavoidably covered by a layer of immunogenic proteins upon injection into blood, such as immunoglobins and complements, which buries the active-targeting ligands and triggers the rapid clearance of NPs by the mononuclear phagocytic system. Low antifouling polyethylene glycol is used to inhibit the formation of the immunogenic corona but it leads to poor cellular uptake and the immunogen-related accelerated blood clearance (ABC) phenomenon in multiple administrations. Here, we develop surface maleimide-modified NPs that covalently conjugate in vivo plasma albumin in its corona upon exposure to blood. The in situ recruited low-immunogenic albumin-enriching corona is capable of protecting maleimide-decorated NPs from phagocytosis in the bloodstream, preventing the ABC phenomenon in the second administration, facilitating NP accumulation in the tumor site/cells by the passive EPR effect and albumin receptor-mediated active targeting, and finally improving the antitumor activity. Such findings suggest that the facile strategy, based on the in situ anchored albumin-enriching corona, is efficient at enabling maleimide-decorated NPs to acquire stealth and tumor-targeting ability.

Stealth CD44-targeted hyaluronic acid supramolecular nanoassemblies for doxorubicin delivery: probing the effect of uncovalent pegylation degree on cellular uptake and blood long circulation.

Stealth active targeting nanoparticles (NPs) usually include two types of ligand sites: ligand anchored on distal ends of the polyethylene glycol (PEG) and ligand buried under pegylated layer. The latter typical case is hyaluronic acid (HA)-based NPs; however, there is little information available for the latter NPs about effect of the optimal density of surface PEG coating on the blood circulation time, cellular uptake and in vivo anticancer activity. Thus, in this study, in order to optimize the anticancer effects of HA-based NPs, we focus on how uncovalent pegylation degree modulates blood circulation time and cellular uptake of HA-based NPs. We firstly designed a new double-hydrophilic copolymer by conjugating HP-ß-cyclodextrin with HA, and this carrier was further pegylated with adamantyl-peg (ADA-PEG) to form inclusion complex HA-HPCD/ADA-PEG, termed as HCPs. The supramolecular nanoassemblies were fabricated by host-guest and polar interactions between HCPs and doxorubicin (Dox), with vitamin E succinate (VES) being a nanobridge. Despite the active recognition between HA and CD44 receptor, the cellular uptake and targeting efficiency of HA-NPs decreased with the increasing peg density, demonstrating HA was partly buried by high density peg coating. However, the high density of peg coating was beneficial to long circulation time, tumor biodistribution and anticancer activity in vivo. NPs with 5% peg coating had the optimal cellular targeting efficiency in vitro and anticancer effects in vivo. The findings suggest that balancing long circulation property and cellular uptake is important to achieve the optimal antitumor efficacy for pegylated HA-based NPs, and that PEG coating densities cannot be extended beyond a certain density for shielding effect without compromising the efficacy of hyaluronic acid targeted delivery.

Critical determinant of intestinal permeability and oral bioavailability of pegylated all trans-retinoic acid prodrug-based nanomicelles: Chain length of poly (ethylene glycol) corona.

Pegylation method is widely used to prolong the blood circulation time of proteins and nanoparticles after intravenous administration, but the effect of surface poly (ethylene glycol) (PEG) chain length on oral absorption of the pegylated nanoparticles is poorly reported. The aim of our study was to investigate the influence of PEG corona chain length on membrane permeability and oral bioavailability of the amphiphilic pegylated prodrug-based nanomicelles, taking all trans-retinoic acid (ATRA) as a model drug. The amphiphilic ATRA-PEG conjugates were synthesized by esterification reaction between all trans-retinoic acid and mPEGs (mPEG500, mPEG1000, mPEG2000, and mPEG5000). The conjugates could self-assemble in aqueous medium to form nanomicelles by emulsion-solvent evaporation method. The resultant nanomicelles were in spherical shape with an average diameter of 13-20 nm. The drug loading efficiency of ATRA-PEG500, ATRA-PEG1000, ATRA-PEG2000, and ATRA-PEG5000 was about 38.4, 26.6, 13.1, and 5.68 wt%, respectively. With PEG chain length ranging from 500 to 5000, ATRA-PEG nanomicelles exhibited a bell shape of chemical stability in different pH buffers, intestinal homogenate and plasma. More importantly, they were all rapidly hydrolyzed into the parent drug in hepatic homogenate, with the half-time values being 0.3-0.4h. In comparison to ATRA solution and ATRA prodrug-based nanomicelles, ATRA-PEG1000 showed the highest intestinal permeability. After oral administration, ATRA-PEG2000 and ATRA-PEG5000 nanomicelles were not nearly absorbed, while the oral bioavailability of ATRA-PEG500 and ATRA-PEG1000 demonstrated about 1.2- and 2.0-fold higher than ATRA solution. Our results indicated that PEG1000 chain length of ATRA-PEG prodrug nanomicelles has the optimal oral bioavailability probably due to improved stability and balanced mucus penetration capability and cell binding, and that the PEG chain length on a surface of nanoparticles cannot exceed a key threshold with the purpose of enhancement in oral bioavailability.