pH-sensitive Release Properties Research Articles

Ionic liquid combined with cationic liposome co-delivers microphthalmia-associated transcription factor small interfering RNA to regulate melanogenesis

Suppressing allele-specific genes using small interfering RNAs (siRNAs) can effectively whiten skin by influencing cellular gene and protein expression. Topical delivery of siRNA is a promising alternative to injections for RNA interference. However, the barrier function of the skin hinders the effective penetration of siRNA. Here, we report, a novel approach to achieve the transdermal delivery of effective siRNA doses using a complementary synergistic strategy of an ionic liquid (IL) and cationic liposome (CL). Microphthalmia-associated transcription factor (MITF) siRNA molecules were formed through electrostatic adsorption of the IL and CL to form positively charged nanocomposites, which were named IL-CL/p-siM. IL-CL/p-siM has a particle size of 171.47 nm, ζ-potential of 29.94 mV, high encapsulation rate of 92.11 %, and pH-sensitive release properties. In vitro studies on porcine skin confirmed the additive/synergistic effect of this strategy in enhancing epidermal and dermal penetration. This combination enabled superior transfection efficiency and cell viability while inhibiting melanin synthesis in skin melanocytes by downregulating the expression of genes downstream of MITF, namely tyrosinase-related protein-1, tyrosinase, and tyrosinase-related protein-2, which are associated with the melanocortin 1 receptor. We also conducted clinical studies that demonstrated its potential in treating melasma and its anti-melanotic efficacy. To summarize, IL-CL/p-siM represents a simple, personalized, and scalable platform for effective local delivery of siRNA to treat skin complications.

Targeted H2S-Mediated Gas Therapy with pH-Sensitive Release Property for Myocardial Ischemia-Reperfusion Injury by Platelet Membrane.

Management of myocardial ischemia-reperfusion injury (MIRI) in reperfusion therapy remains a major obstacle in the field of cardiovascular disease, but current available therapies have not yet been achieved in mitigating myocardial injury due to the complex pathological mechanisms of MIRI. Exogenous delivery of hydrogen sulfide (H2S) to the injured myocardium can be an effective strategy for treating MIRI due to the multiple physiologic functions of H2S, including anti-inflammatory, anti-apoptotic, and mitochondrial protective effects. Here, to realize the precise delivery and release of H2S, we proposed the targeted H2S-mediated gas therapy with pH-sensitive release property mediated by platelet membranes (PMs). In this study, a biomimetic functional poly(lactic-co-ethanolic acid) nanoparticle (RAPA/JK-1-PLGA@PM) was fabricated by loading rapamycin (RAPA; mTOR inhibitor) and JK-1 (H2S donor) and then coated with PM. Invitro observations were conducted including pharmaceutical evaluation, H2S release behaviors, hemolysis analysis, serum stability, cellular uptake, cytotoxicity, inhibition of myocardial apoptosis, and anti-inflammation. Invivo examinations were performed including targeting ability, restoration of cardiac function, inhibition of pathological remodeling, and anti-inflammation. RAPA/JK-1-PLGA@PM was successfully prepared with good size distribution and stability. Utilizing the natural infarct-homing ability of PM, RAPA/JK-1-PLGA@PM could be effectively targeted to the damaged myocardium. RAPA/JK-1-PLGA@PM continuously released H2S triggered by inflammatory microenvironment, which could inhibit cardiomyocyte apoptosis, realize the transition of pro-inflammation, and alleviate myocardial injury demonstrated in hypoxia/reoxygenation myocardial cell invitro. Precise delivery and release of H2S attenuated inflammatory response and cardiac damage, promoted cardiac repair, and ameliorated cardiac function proven in MIRI mouse model invivo. This research outlined the novel nanoplatform that combined immunosuppressant agents and H2S donor with the pH-sensitive release property, offering a promising therapeutic for MIRI treatment that leveraged the synergistic effects of gas therapy.

Preparation of Self-Assembled, Curcumin-Loaded Nano-Micelles Using Quarternized Chitosan-Vanillin Imine (QCS-Vani Imine) Conjugate and Evaluation of Synergistic Anticancer Effect with Cisplatin.

Nano-micelles are self-assembling colloidal dispersions applied to enhance the anticancer efficacy of chemotherapeutic agents. In this study, the conjugate of quarternized chitosan and vanillin imine (QCS-Vani imine) was synthesized using the reaction of a Schiff base characterized by proton-NMR (1HNMR), UV-Vis spectroscopy, and FT-IR. The critical micelle concentration (CMC), particle size, and zeta potential of the resulting product were determined. The QCS-Vani imine conjugate was used as a carrier for the development of curcumin-loaded nano-micelles, and their entrapment efficiency (%EE), drug-loading capacity (%LC) and in vitro release were investigated using HPLC analysis. Moreover, the nano-micelles containing curcumin were combined with various concentrations of cisplatin and evaluated for a possible anticancer synergistic effect. The anticancer activity was evaluated against lung cancer A549 and mouse fibroblast L929 cell lines. The percent yield (%) of the QCS-Vani imine conjugate was 93.18%. The curcumin-loaded QCS-Vani imine nano-micelles were characterized and found to have a spherical shape (by TEM) with size < 200 nm (by DLS) with high %EE up to 67.61% and %LC up to 6.15 ± 0.41%. The loaded lyophilized powder of the nano-micelles was more stable at 4 °C than at room temperature during 120 days of storage. pH-sensitive release properties were observed to have a higher curcumin release at pH 5.5 (cancer environment) than at pH 7.4 (systemic environment). Curcumin-loaded QCS-Vani imine nano-micelles showed higher cytotoxicity and selectivity toward lung cancer A549 cell lines and exhibited lower toxicity toward the normal cell (H9C2) than pure curcumin. Moreover, the curcumin-loaded QCS-Vani imine nano-micelles exhibited an enhanced property of inducing cell cycle arrest during the S-phase against A549 cells and showed prominently induced apoptosis in lung cancer cells compared to that with curcumin. The co-treatment of cisplatin with curcumin-loaded QCS-Vani imine nano-micelles presented an enhanced anticancer effect, showing 8.66 ± 0.88 μM as the IC50 value, in comparison to the treatment with cisplatin alone (14.22 ± 1.01 μM). These findings suggest that the developed QCS-Vani imine nano-micelle is a potential drug delivery system and could be a promising approach for treating lung cancer in combination with cisplatin.

Preparation and Properties of Natural Polysaccharide-Based Drug Delivery Nanoparticles.

In recent years, natural polysaccharides have been widely used in the preparation of drug delivery systems. In this paper, novel polysaccharide-based nanoparticles were prepared by layer-by-layer assembly technology using silica as a template. The layers of nanoparticles were constructed based on the electrostatic interaction between a new pectin named NPGP and chitosan (CS). The targeting ability of nanoparticles was formed by grafting the RGD peptide, a tri-peptide motif containing arginine, glycine, and aspartic acid with high affinity to integrin receptors. The layer-by-layer assembly nanoparticles (RGD-(NPGP/CS)3NPGP) exhibited a high encapsulation efficiency (83.23 ± 6.12%), loading capacity (76.51 ± 1.24%), and pH-sensitive release property for doxorubicin. The RGD-(NPGP/CS)3NPGP nanoparticles showed better targeting to HCT-116 cells, the integrin αvβ3 high expression human colonic epithelial tumor cell line with higher uptake efficiency than MCF7 cells, the human breast carcinoma cell line with normal integrin expression. In vitro antitumor activity tests showed that the doxorubicin-loaded nanoparticles could effectively inhibit the proliferation of the HCT-116 cells. In conclusion, RGD-(NPGP/CS)3NPGP nanoparticles have potential as novel anticancer drug carriers because of their good targeting and drug-carrying activity.

The enhanced encapsulation, release, and oral hypoglycemic performance of a biomacromolecule surface modified insulin-loaded halloysite nanocomposite: an in vitro and in vivo study

To overcome the drawbacks of oral administration of insulin, a surface-modified insulin-loaded nanocomposite was designed and prepared in this work. Halloysite nanotubes (HNTs) were employed to improve the insulin encapsulation, PEG-CS and hydroxypropyl methyl cellulose phthalate (HPMCP) were selected to surface modify the insulin-loaded HNTs to adjust the release of insulin. As a result, the insulin-loaded HNTs/PEG-CS/HPMCP NCs had good biocompatibility, relatively high drug loading, and pH-sensitive release properties. Oral administration of the NCs produced an effective and relative long-time hypoglycemic effect. Therefore, these NCs can be a promising delivery system to improve the oral bioavailability of insulin.

Liposomal Co-delivery of PD-L1 siRNA/Anemoside B4 for Enhanced Combinational Immunotherapeutic Effect.

Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)─AB4/siP-c-L─and evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.

Solubilized chlorin e6-layered double hydroxide complex for anticancer photodynamic therapy

BackgroundLayered double hydroxides (LDHs) are one type of 2-dimensional material with unique structure and strongly positive surface charge. Particularly, LDHs can be exfoliated by mono-layered double hydroxides (MLHs) as a single layer, showing an increased surface area. Therefore, there is a large focus on LDHs for drug delivery applications. Furthermore, most photosensitizers are hydrophobic that they cannot be soluble in aqueous solvents. Herein, we designed a simple way to solubilize hydrophobic photosensitizers by MLH with electrostatic interactions for anticancer photodynamic therapy (PDT), which has tremendous therapeutic advantages. The photosensitizer solubilized via loading on the MLH exhibited fluorescence and singlet oxygen-generation activities in aqueous solvent without chemical modification, resulting in photo-mediated anticancer treatment.MethodsNegatively charged hydrophobic photosensitizers, chlorin e6 (Ce6) were solubilized by loading on the MLHs through the electrostatic interaction between positively charged MLHs. MLH/Ce6 complexes evaluated for physico-chemical characterization, pH-sensitive release property, in vitro photocytotoxicity, and in vivo tumor ablation.ResultsThe photosensitizer solubilized via MLH exhibited fluorescence intensity and singlet-oxygen generation activities in aqueous solvent without chemical modification, resulting photocytotoxicity in cancer cells. The encapsulation efficiency of Ce6 increased to 21.2% through MLH compared to 0.6% when using LDH. In tumor-bearing mice, PDT with solubilized MLH/Ce6 indicated a tumor-suppressing effect approximately 3.4-fold greater than that obtained when Ce6 was injected alone.ConclusionsThis study provided the solubilized Ce6 by the MLH in a simple way without chemical modification. We demonstrated that MLH/Ce6 complexes would have a great potential for anticancer PDT.

An innovative wax-based enteric coating for pharmaceutical and nutraceutical oral products.

In this work, a novel enteric coating based on natural waxes and alginate was reported. Initially, theophylline tablets were coated with emulsified ceresin wax in heated aqueous alginate solution using a fluidised bed coating technology. A coating level of 10% proved sufficient to prevent tablets from uptaking gastric medium (<5%) and produced a delayed release profile that complies to the pharmacopeial criteria of enteric coating release. Then, a wide range of emulsions based on other natural waxes (white beeswax, yellow beeswax, cetyl palmitate, carnauba wax or rice bran wax) yielded coatings with similar disintegration times and release profiles. Interestingly, the ceresin-based coating showed a superior performance at inhibiting acid uptake and enabling highly pH-responsive drug release in comparison to different commercially available GRAS enteric coating products (Eudraguard® Control, Swanlac® ASL10, and Aquateric™ N100). The coating was stable for 6months at 30°C and 65% RH. This innovative approach of applying hot O/W emulsion of natural waxes yielded an aesthetically attractive and stable coating with gastric protection and pH-sensitive release properties. The novel coating can be an efficient and promising alternative to overcome the shortcomings of current GRAS grade enteric coating products.

Engineering pectin-based hollow nanocapsules for delivery of anticancer drug

Multifunctional capsules have great applications in biomedical fields. In this study, novel polysaccharide-based nanocapsules were prepared via a layer-by-layer technique using silica as the templates. The shell was constructed based on the electrostatic interactions between pectin and chitosan. The pectin-chitosan nanocapsules ((Pec/Cs)3Pec) could keep good colloidal stability within 96h in PBS solution and 48h in BSA solution. Meanwhile, the nanocapsules exhibited a high drug loading and pH-sensitive release property for doxorubicin hydrochloride. Moreover, (Pec/Cs)3Pec nanocapsules had no cytotoxicity to both human hepatocellular carcinoma cells (HepG2 cells) and mouse fibroblast cells (L929 cells). More importantly, (Pec/Cs)3Pec nanocapsules could be more easily uptaken by HepG2 cells when compared with L929 cells. In vitro anticancer activity tests indicated the carriers could effectively kill HepG2 cells. Overall, (Pec/Cs)3Pec nanocapsules have great potential as a novel anticancer drug carrier as a result of their pH-sensitivity, good colloidal stability and anticancer activity.

A large-inner-diameter multi-walled carbon nanotube-based dual-drug delivery system with pH-sensitive release properties.

A novel dual-drug delivery system (DDDS) for cancer chemotherapy has been established by employing highly purified and mildly oxidized large-inner-diameter multi-walled carbon nanotubes (LID-MWCNTs) as the vector. The LID-MWCNTs were modified with the antitumor drugs, cisplatin (CDDP) and doxorubicin (DOX). CDDP was encapsulated inside the nanotube vectors by a wet-chemical approach while DOX was attached to the external surfaces through non-covalently interaction. The loading efficiencies of CDDP and DOX were as high as 84.56 and 192.67%, respectively. Notably, after CDDP was encapsulated inside the nanotubes, a three-level blocking strategy, which included polyethylene glycol, folic acid and DOX, was employed to block the CDDP exits at different levels. The pH-sensitive release profile of CDDP was demonstrated using a modified characterization method, as well as that of DOX. Finally, the anticancer activity of the DDDS on MCF-7 cells was tested and a synergistic effect was recorded. This work is part of our LID-MWCNTs based drug delivery system studies, and provides a basis for developing a novel comprehensive antitumor treatment that combines chemotherapy and photothermal therapy.

Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon

In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease.

A Novel Hollow Hydroxyapatite Microspheres/Chitosan Composite Drug Carrier for Controlled Release

A novel composite drug carrier with excellent sustained and pH-sensitive release performance was prepared by mixing hollow hydroxyapatite (HA) microspheres and chitosan solution with pH-sensitive characteristics. The hollow HA microspheres with mesopores filled on their multilayered spherical shell were obtained by converting borate glass with a novel composition of 19Na2O-17CaO-64B2O3 (wt%). The structure, phase composition and morphology of HA microspheres were characterized by SEM, SEM-EDS, XRD, FTIR and N2 adsorption-desorption measurements. The results indicated that the HA microspheres were B-type carbonated HA with hollow structure, in which the carbonate ions occupied the phosphate sites. The drug release results indicated that the HA microspheres generated burst release at initial stage. Coating the hollow HA microspheres with chitosan (CS) reduced the vancomycin release amount and release rate significantly. Meanwhile, the release profile of vancomycin into PBS with different pH value indicated that the CS-coated composite drug carrier shows pH-sensitive release property. The cumulative percentage of vancomycin released into PBS from the CS (20 g/L)-coated composite drug carrier was 85.63%, 65.85% and 71.85% for pH 6.0, 7.4, 8.5, respectively.

Epirubicin-Complexed Polypeptide Micelle Effectively and Safely Treats Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide. Epirubicin (EPI) once acted as a main agent for HCC chemotherapy. However, the dosage-dependent side effects seriously limit its application in clinic. The purpose of this study is to develop an effective nanocarrier to improve the efficacy and overcome the limitations of EPI. In this regard, the EPI-complexed micelle (i.e., mPEG-b-PGA/EPI) was prepared via the electrostatic interaction between the amino group in EPI and the carboxyl group in PGA segment of methoxy poly(ethylene glycol)-block-poly(l-glutamic acid) (mPEG-b-PGA), and the subsequent hydrophobic interaction among PGA/EPI complexes. The micelle appeared spherical with a diameter at around 90 nm and possessed a pH-sensitive release property of payload. The cytotoxicity and hemolysis assays in vitro, and the maximum tolerated dose tests in vivo confirmed that mPEG-b-PGA was a kind of safe material with excellent biocompatibility, while the drug-loaded micelle could obviously improve the tolerance of EPI. In addition, mPEG-b-PGA/EPI possessed significantly enhanced antitumor efficacy and security toward the H22-xenografted HCC murine model at macroscopic and microscopic levels compared with free EPI. All these results strongly indicate that mPEG-b-PGA/EPI may be a promising nanoplatform for EPI delivery in the chemotherapy of HCC.

Synthesis, characterization and evaluation of pH sensitive chitosan-dexamethasone prodrug in vitro

[Objective]To synthesise the prodrug of chitosan-dexamethasone with pH sensitive release property.[Methods]The chitosan-dexamethasone prodrug was prepared by covalently linking via hydrazone bonds,and the structure of the prodrug was verified by 1H-NMR.The nanoprodrug was prepared by dialyse method,and the size and morphology were observed by dynamic light scattering and transmission electron microscope.The drug release in different pH of the prodrug was evaluated.[Results]The prodrug was synthesized and confirmed as expected.The size of the prodrug nanoparticle was about 100 ～ 250 nm,and the prodrug realeased faster in pH 5.8 than in pH 7.4 PBS solution.Conclsion The pH sensitve chitosan-dexamethasone prodrug is synthesized successfully,which has potential application in the rheumatoid arthritis treatment. Key words: Chitosan; Dexamethasone; Prodrug; pH sensitve; Nanopartical

Synthesis of β-cyclodextrin modified chitosan–poly(acrylic acid) nanoparticles and use as drug carriers

β-Cyclodextrin modified chitosan–poly(acrylic acid) nanoparticles (CS–PAACD NPs) were obtained by polymerizing acrylic acid (AA) and β-cyclodextrin (β-CD) substituted acrylic acid (AACD) in chitosan (CS) solution. These CS–PAACD NPs, characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM) as well as atomic force microscopy (AFM), were quite small in size about 40–50nm. The size and the microstructure of these CS–PAACD NPs could be accurately controlled by changing the ration of AACD to AA. As the ratio of AACD to AA increased, the size of these NPs decreased. These as-prepared CS–PAACD NPs showed enhanced solubility for paclitaxel (PTX) in aqueous solution and exhibited a typical pH-sensitive release property for the encapsulated drug in vitro. The presence of the β-cyclodextrin inside the CS–PACD NPs greatly enhanced the ability to load hydrophobic drugs, which significantly broadened the application of CS–PAACD NPs in biomedical fields.

Preparation and pH-Sensitive Release Behavior of Alginate/Activated Carbon Composite Magnetic Hydrogels

The alginate-based hydrogel was prepared as a pH-sensitive drug delivery system. To enhance the drug loading capacity, activated carbon was introduced as a drug absorbent. The iron oxide was incorporated into the alginate matrix for the magnetic transferring to the target organ. The activated carbon and iron-oxide were dispersed uniformly in the alginate hydrogel. The drug release from the alginate/activated carbon composite hydrogel was carried out in various pH conditions with vitamin B12 and Lactobacillus lamnosers as model drugs. The fast and sustainable release of drug was observed in the basic condition due to the pH-sensitive solubility of alginate. The novel drug delivery system having pH-sensitive release property and magnetic movement to target place was developed by using the alginate/activated carbon composite magnetic hydrogels.

PH-dependent release property of alginate beads containing calcium carbonate particles

Alginate bead containing calcium carbonate particle were prepared by dropping the suspension of alginate/calcium carbonate (4/1, w/w) into aqueous solution of CaCl2 (0.1 M). The pH-dependent release property of the bead was observed for 12 h using blue dextran as a model drug. The release increased up to 4 h in a saturation manner. When no calcium carbonate was contained, the release exhibited no marked variation with pH and the values were 27–39%. On the other hand, in case calcium carbonate was included in the matrix of alginate beads, intensive release(40–50%) was achieved in acidic and neutral conditions and the degrees of release were suppressed in alkali conditions and the values were ∼20%. The pH-sensitive release property is possibly because the particles of calcium carbonate embedded in the matrix of beads were leached out in acidic and neutral conditions, leaving cavities in the matrix. The cavities are likely to be main pathways for the release of blue dextran.