Nanoparticles with Active Targeting Ability and Acid Responsiveness for an Enhanced Antitumor Effect of Docetaxel.

Docetaxel (DOC) is commonly used in cancer treatment, especially for breast cancer. However, there are severe side effects in clinical application. In order to deliver docetaxel more effectively, a novel, active targeting acid-responsive polymer called cRGD-PAE-PEG-DSPE was developed. The polymer structure incorporated poly(ethylene glycol) (PEG) as the hydrophilic segment, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) as the hydrophobic segment, and poly(ß-amino ester) (PAE) as the acid-responsive group, which was grafted onto the PEG. Furthermore, c(RGDyC) was grafted onto PAE to confer active targeting capability. Through self-assembly, docetaxel was encapsulated in RAED@DOC. Through in vitro experiments, it was confirmed that RAED@DOC had good serum stability and acid responsiveness, as well as enhanced uptake by MDA-MB-231 cells. Additionally, the antitumor efficiency in vivo and histopathological analysis showed that RAED@DOC exhibited higher antitumor activity and lower systemic toxicity in comparison to free docetaxel. These results suggested that RAED@DOC had considerable potential clinical use.

A Redox-Activatable and Targeted Photosensitizing Agent to Deliver Doxorubicin for Combining Chemotherapy and Photodynamic Therapy.

Currently, tumors have become a serious disease threatening human health and life in modern society. Photo-chemo combination therapy is considered to be an important method to improving the efficiency of tumor treatment, especially in the treatment of multi-drug-resistant tumors. However, the application of photo-chemo combination therapy has been limited by the poor water solubility of photosensitizers, low tumor targeting, and high side effects of chemotherapy drugs. In order to solve these problems, a smart nano drug delivery platform FA-PEG-ss-PLL(-g-Ce6) designed and synthesized by us. The smart nano drug carrier uses folic acid (FA) as the targeting group, polyethylene glycol (PEG) as the hydrophilic end, Ce6-grafted polylysine (PLL(-g-Ce6)) as the hydrophobic end, and Chlorin e6 (Ce6) as the photosensitizer of photodynamic therapy, and it connects PEG to PLL by a redox-responsive cleavable disulfide linker (-ss-). Finally, the combination of tumor chemotherapy and photodynamic therapy (PDT) is realized by loading with anticancer drug doxorubicin (DOX) to the intelligent carrier. In vitro experiments showed that the drug loading content (DLC%) of DOX@FA-PEG-ss-PLL(-g-Ce6) nanoparticles (DOX@FPLC NPs) was as high as 14.83%, and the nanoparticles had good serum stability, reduction sensitivity and hemocompatibility. From the cytotoxicity assays in vitro, we found that under 664 nm laser irradiation DOX@FPLC NPs showed stronger toxicity to MCF-7 cells than did DOX, Ce6 + laser, and DOX + Ce6 + laser. Moreover, the antitumor efficiency in vivo and histopathological analysis showed that DOX@FPLC NPs under 664 nm laser irradiation exhibited higher antitumor activity and lower systemic toxicity than single chemotherapy. These results suggested that the FA-PEG-ss-PLL(-g-Ce6) nano drug delivery platform has considerable potential for the combination of chemotherapy and PDT.

A Combined Utilization of Plasdone-S630 and HPMCAS-HF in Ziprasidone Hydrochloride Solid Dispersion by Hot-Melt Extrusion to Enhance the Oral Bioavailability and No Food Effect.

The purpose of this study was to research a novel combination of Plasdone-S630 and HPMCAS-HF as hot-melt carrier used in ziprasidone hydrochloride for enhanced oral bioavailability and dismissed food effect. Ziprasidone hydrochloride solid dispersion (ZH-SD) was prepared by hot-melt extrusion technique, and its optimized formulation was selected by the central composite design (CCD), which was characterized for powder X-ray diffraction (PXRD), fourier transform infrared spectroscopy (FTIR), in vitro dissolution study, and stability study. Finally, the in vivo study in fasted/fed state was carried out in beagle dogs. Based on PXRD analysis, HME technique successfully dispersed ziprasidone with a low crystallinity hydrochloride form in the polymers. According to the analysis of FTIR, hydrogen bonds were formed between drug and polymers during the process of HME. Without any noticeable bulk, crystalline could be found from the micrograph of ZH-SD when analyzed the result of scanning electron microscope (SEM). Pharmacokinetics studies indicated that the bioavailability of ZH-SD formulation had no significant difference in fasted and fed state, and the Cmax and AUC of ZH-SD were two fold higher than Zeldox® in fasted state. This result indicated that ziprasidone has achieved a desired oral bioavailability in fasted state and no food effect.

Formulation optimization and pharmacokinetics evaluation of oral self-microemulsifying drug delivery system for poorly water soluble drug cinacalcet and no food effect.

The present research indicated that a new self-microemulsifying drug delivery systems (SMEDDS) were used to reduce the food effect of poorly water-soluble drug cinacalcet and enhance the bioavailability in beagle dogs by oral gavage. Ethyl oleate, OP-10, and PEG-200 was selected as the oil phase, surfactant and co-surfactant of cinacalcet-SMEDDS by the solubility and phase diagram studies. Central Composite Design-Response Surface Methodology was used to determine the ratio of surfactant and co-surfactant, the amount of oil for optimizing the SMEDDS formation. The prepared formulations were further characterized by the droplet size, self-microemulsifying time, zeta potential, polydispersity index (PDI), and robustness to dilution. The in vitro release profile of cinacalcet-SMEDDS was determined in four different release medium and in fasted state and fed state of simulated gastrointestinal fluid. Cinaclcet-SMEDDS were implemented under fed and fasted state in dogs and product REGPARA® was used as a comparison to the prepared formulation in the pharmacokinetics. The result showed the components of SMEDDS, the amount of oil, the ratio of surfactant, and co-surfactant was optimized using solubility, pseudo-ternary phase diagram studies, and response surface methodology. In vitro drug release studies indicated that the cinacalcet-SMEDDS eliminated the effect of pH variability in release medium and variational gastroenteric environments with improved drug release performance. Pharmacokinetic studies revealed that the profiles of cinacalcet-SMEDDS were similar both in the fasted and fed state compared with commercial product, indicating the formulation significantly promoted the absorption, enhanced bioavailability and had no food effect essentially. It is concluded that poorly water-soluble drug cinacalcet was improved in the solubility and bioavailability by using a successful oral dosage form the SMEDDS, and eliminated food effect as well.

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state.

OBJECTIVE: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs). METHODS: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control. RESULTS: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5 min. Pharmacokinetic study showed that the AUC(0-∞) and Cmax for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption. CONCLUSION: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.

A hydrogel based on nanocellulose/polydopamine/gelatin used for the treatment of MRSA infected wounds with broad-spectrum antibacterial and antioxidant properties and tissue suitability.

Most wound dressings encounter a series of problems when dealing with the bacterial infection of wounds, for example, the antibacterial and antioxidant capacities, comfort, and mechanical properties are not suitable to meet clinical requirements. Here, we synthesized ε-polylysine-grafted nanocellulose (NCF-EPL) and polydopamine (PDA) nanoparticles and embedded them in genipin-cross-linked gelatin to prepare a hydrogel (NCF-EPL/GTP/PDA). In this system, the embedded NCF-EPL and PDA interact with the gelatin matrix to form a hydrogel with excellent physical properties. The hydrogel has broad-spectrum antibacterial abilities and good antioxidant performance, and it can effectively promote cell proliferation. Full-thickness MRSA-infected skin wound healing experiments clearly show that the NCF-EPL/GTP/PDA hydrogel can significantly accelerate the healing of infected wounds via killing bacteria and reducing inflammation, and secondary damage caused by adhesion during dressing use is effectively avoided. In short, the hydrogel provides a new method for overcoming the shortcomings of traditional dressings, and this approach provides further solutions for the selection of clinical dressings for healing wounds.

Calcium alginate/PNIPAAm hydrogel with body temperature response and great biocompatibility: Application as burn wound dressing.

Deep burns often do not heal easily, because the dermis of the skin is severely damaged, leading to severe inflammation and bacterial infection. Therefore, it is of great clinical significance to develop a dressing that promotes the healing process of deep burn wound. In this study, we used N-isopropyl acrylamide, sodium alginate and calcium chloride as the main materials, a series of calcium alginate/ poly (N-isopropyl acrylamide)(NIPAAm) hydrogel (CAPH) with different component ratios were synthesized. Its swelling properties, temperature response properties, rheological properties, biocompatibility properties, and in vitro drug release properties were investigated. Based on the above conditions, the CAPH(sodium alginate:NIPAAm = 2:15) with the best comprehensive performance was selected, which has a good biocompatibility. In addition, 0.02 % (w/v) mupirocin was loaded in CAPH. The temperature-responsive property of PNIPAAm in CAPH at 34 °C not only allowed the CAPH to rapidly release the drug under to prevent infection, but also to assist in wound contraction. Application of CAPH to localized wounds of deep second-degree burns in mice showed a faster healing rate and tissue regeneration. At the same time, collagen recovery was enhanced, collagen bundles were arranged in an orderly manner, and the scarring was not obvious after 16 days. Therefore, this research prepared a new safe and effective biomaterial.

RGD-targeted redox responsive nano micelle: co-loading docetaxel and indocyanine green to treat the tumor.

Cancer, also known as a malignant tumor, has developed into a type of disease with the highest fatality rate, seriously threatening the lives and health of people. Chemotherapy is one of the most important methods for the treatment of cancer. However, chemotherapy drugs have some problems, such as low solubility and lack of targeting, which severely limit their clinical applications. To solve these problems, we designed a block copolymer that has a disulfide bond response. The polymer uses RGD peptide (arginine-glycine-aspartic acid) as the active targeting group, PEG (polyethylene glycol) as the hydrophilic end, and PCL (polycaprolactone) as the hydrophobic end. Then we utilized the amphiphilic polymer as a carrier to simultaneously deliver DOC (docetaxel) and ICG (indocyanine green), to realize the combined application of chemotherapy and photothermal therapy. The antitumor efficacy in vivo and histology analysis showed that the DOC/ICG-loaded micelle exhibited higher antitumor activity. The drug delivery system improved the solubility of DOC and the stability of ICG, realized NIR-guided photothermal therapy, and achieved an ideal therapeutic effect.

PEGylated Triacontanol Substantially Enhanced the Pharmacokinetics of Triacontanol in Rats.

Triacontanol (TA), a natural compound with various health benefits, is extensively used as a nutritional supplement. The therapeutic and nutraceutical applications of TA are limited due to its poor aqueous solubility. PEGylated triacontanol (PEGylated TA) was designed to improve the solubility and pharmacokinetics of TA. After PEGylation, the solubility (∼250 g·L-1 versus 9 × 10-14 g·L-1), body residence (MRT, 9.40 ± 2.03 h versus 2.59 ± 0.705 h, p < 0.001), and systemic exposure (AUC0-inf, 29.1 ± 5.33 µM·h versus 0.529 ± 0.248 µM·h, p < 0.001) of TA were all significantly increased compared to pristine TA. When intravenously administered (6.85, 22.8, and 68.5 µmol·kg-1) in rats, PEGylated TA exhibited a slow clearance (44.8 ± 8.62, 47.9 ± 5.18, and 46.9 ± 16.5 mL·h-1·kg-1), long elimination half-life (8.76 ± 0.96, 10.4 ± 1.66, and 11.1 ± 2.81 h), and abundant systemic exposure (AUC0- t, 155 ± 24.2, 523 ± 56.2, and 1709 ± 245 µM·h). Meanwhile, its metabolite TA showed a high AUC0- t (28.4 ± 5.14, 151 ± 25.4, and 797 ± 184 µM·h) and slow elimination ( t1/2, 10.1 ± 2.03, 7.78 ± 1.74, and 6.82 ± 0.58 h). Our results demonstrated that PEGylated TA has superior pharmacokinetics, which enhanced its nutritional and pharmacodynamic potency, and thus warrants further investigations.

Characterization and evaluation of self-nanoemulsifying sustained-release pellet formulation of ziprasidone with enhanced bioavailability and no food effect.

The purpose of this work was to develop self-nanomulsifying drug delivery systems (SNEDDS) in sustained-release pellets of ziprasidone to enhance the oral bioavailability and overcome the food effect of ziprasidone. Preformulation studies including screening of excipients for solubility and pseudo-ternary phase diagrams suggested the suitability of Capmul MCM as oil phase, Labrasol as surfactant, and PEG 400 as co-surfactant for preparation of self-nanoemulsifying formulations. Preliminary composition of the SNEDDS formulations were selected from the pseudo-ternary phase diagrams. The prepared ziprasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized ziprasidone-SNEDDS were used to prepare ziprasidone-SNEDDS sustained-release pellets via extrusion-spheronization method. The pellets were characterized for SEM, particle size, droplet size distribution and zeta potential. In vitro drug release studies indicated the ziprsidone-SNEDDS sustained-release pellets showed sustained release profiles with 90% released within 10 h. The ziprsidone-SNEDDS sustained-release pellets were administered to fasted and fed beagle dogs and their pharmacokinetics were compared to commercial formulation of Zeldox as a control. Pharmacokinetic studies in beagle dogs showed ziprasidone with prolonged actions and enhanced bioavailability with no food effect was achieved simultaneously in ziprsidone-SNEDDS sustained-release pellets compared with Zeldox in fed state. The results indicated a sustained release with prolonged actions of schizophrenia and bipolar disorder treatment.

PLGA nanoparticles for the oral delivery of 5-Fluorouracil using high pressure homogenization-emulsification as the preparation method and in vitro/in vivo studies.

The objective of the present study was to incorporate the hydrophilic anti-cancer drug 5-Fluorouracil(5-FU) into poly(lactide-co-glycolide) (PLGA) nanoparticles(NP) to improve the oral bioavailability. Owing to the high solubility of 5-FU in basic water, the water-in-oil-in-water (w/o/w) emulsification process has been chosen as one of the most appropriate method for the encapsulation of 5-FU, and the ammonia solution was used as the inner aqueous phase solvent to increase the solubility of 5-FU. In order to reach submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, we prepared 5-FU loaded PLGA-NP by a high-pressure emulsification-solvent evaporation process. The PLGA-NPs were characterized with respect to their morphology, particle size, size distribution, 5-FU encapsulation efficiency, in vitro and in vivo studies in rats. In vitro release of 5-FU from nanoparticles appeared to have two components with an initial rapid release due to the surface associated drug and followed by a slower exponential release of 5-FU, which was dissolved in the core. The in vivo research was studied in male Sprague-Dawley rats after an oral 5-FU dose of 45 mg/kg. Single oral administration of 5-FU loaded PLGA-NP to rats produced bioavailability, which was statistically higher than 5-FU solution as negative control. And the MRT (mean residence time) of 5-FU loaded PLGA-NP was significantly (P < 0.05) modified. Thus, it is possible to design a controlled drug delivery system for oral 5-FU delivery, improving therapy efficiency by possible reduction of time intervals between peroral administrations and reduction of local gastrointestinal side effects.