pH-sensitive Release Behavior Research Articles

Design and characterization of a novel pH-sensitive biocompatible and multifunctional nanocarrier for in vitro paclitaxel release

Breast cancer is one of the main reasons of women's mortality. A novel ternary combination of ZnAl-layered double hydroxides (LDH), cobalt ferrite (CoFe2O4) and N-graphene quantum dots (N-GQDs) proposes a pH-sensitive multifunctional nanocomposite that can improve therapeutic features of each compound; this is a notable strategy to make biocompatible materials with unique properties for paclitaxel (PTX) delivery in breast cancer cells. For proving the surface modification process of materials, electrochemical techniques including cyclic voltammetry (CV) and differential pulse voltammetry (DPV) were carried out. By coating PEG on the surface of the N-GQDs/CoFe2O4/LDH, it developed a drug delivery system with low toxicity, an excellent encapsulation efficiency 88.4%, drug loading capacity of ca. 31%, and slow and sustained release behavior (9% after 72 h) under normal physiological conditions. Besides, a high drug release (~69%) at low-pH as a model of the extracellular tumor environment indicated a pH-sensitive release behavior. Moreover, cell viability assay proved the negligible cytotoxicity on normal cells (L929) and the improved growth inhibition effect of PTX/N-GQDs/CoFe2O4/LDH nanocarrier on MCF7 cancer cells. Blood compatibility test values with respect to red blood cell aggregation (RBC), coagulation prothrombin time (PT), activated partial thromboplastin time (APTT), and complement activation (C3 and C4 levels) remained within normal ranges without toxicity effect on RBCs and complement factors. Overall, this novel designed PTX/N-GQDs/CoFe2O4/LDH nanocarrier with tremendously biocompatible, slow-release and pH-dependent features could be considered as a theranostic candidate for various anticancer drugs delivery and cancer therapy.

In vitro/in vivo evaluation of pH-sensitive Gambogenic acid loaded Zein nanoparticles with polydopamine coating

As one of the active pharmaceutical ingredients in Gamboge, Gambogenic acid (GNA) has shown diverse anti-tumor activities. To reduce the vascular irritation of GNA and improve its water solubility, tumor targeting, and bioavailability, GNA loaded Zein nanoparticles (GNA@Zein NPs) was further coated by polydopamine (PDA) to develop GNA@Zein-PDA NPs by anti-solvent precipitation and surface modification. The results showed that particle size and Zeta potential of GNA@Zein-PDA NPs were about 310nm and -40.8mV with core-shell morphology confirmed by TEM. GNA@Zein-PDA NPs increased the water solubility of GNA by more than 700 times and showed pH-sensitive release behavior in PBS with pH 6.86. In vitro cytotoxicity tests showed that GNA@Zein-PDA NPs had higher inhibitory activity on HepG2 cells than free GNA, and their IC50 were 1.59μg/mL and 9.89μg/mL, respectively. Additionally, the hemolysis and vascular irritation assay showed that GNA@Zein-PDA NPs had good cytocompatibility and reduced the irritation of GNA to blood vessels. Moreover, the in vivo pharmacokinetic experiments exhibited that the Cmax and AUC0-t of GNA@Zein-PDA NPs were significantly improved approximately by 2.09-fold and 3.48-fold over that of GNA, respectively. In conclusion, GNA@Zein-PDA NPs solve many defects of GNA and provide a tumor-targeting drug delivery for GNA.

Photocatalytic property and pH-response behavior of modified ZnO electrospun nanofibers grafted with poly(methyl methacrylate)

ZnO nanomaterials have been widely studied in medical and biological fields owing to their better biocompatibility, pH-responsibility and higher photocatalytic ability as drug carriers and disease therapy agent. However, the unstability of ZnO nanomaterials within aqueous solution restricts the applications of it to some extent. In this work, ZnO nanofibers with relative higher porosity were fabricated by electrospinning to improve the load capacity as carriers, and then were modified by hydrophobic poly(methyl methacrylate) (PMMA) through graft polymerization on the surface to improve their stability in aqueous solution. Observations on the morphologies of the nanofibers by SEM showed that the surface modification of PMMA well enhanced the water-stability of ZnO nanofibers. Moreover, the photocatalytic degradation of Rhodamine B was investigated, and pH sensitive release behaviors were studied in details under different pH values, by taking Nifedipine as drug model. The results indicated that PMMA modified ZnO nanofibers showed obvious photocatalytic performances and maintained relative excellent pH-response properties. These findings all suggested that the modified ZnO nanofibers might be one kind of excellent material as medical carrier or therapy agents.

PH sensitive doxorubicin-loaded nanoparticle based on Radix pseudostellariae protein-polysaccharide conjugate and its improvement on HepG2 cellular uptake of doxorubicin

Nanoparticles based on Radix pseudostellariae protein-polysaccharide conjugates were self-assembled via pH adjustment and thermal treatment. The fabricated nanoparticles (CP3) were spherical with narrow size distribution of 125.0 nm in diameter. The doxorubicin (DOX) -loaded CP3 nanoparticles exhibited pH-sensitive release behavior and accelerated the release of DOX under the acidic pH simulating tumor microenvironment and endosomal pH. In HepG2 uptake studies, CP3-DOX nanoparticles notably improved the internalization of DOX, which was 1.56-fold compared with free DOX. CP3-DOX nanoparticles could serve as P-glycoprotein efflux pump inhibitor and be internalized into HepG2 cells via clathrin-dependent endocytosis. Moreover, the cytotoxicity effect of DOX on HepG2 cells was elevated after the encapsulation by CP3, with a lower IC50 value of 0.25 μg/mL. The findings suggested that the pH-sensitive CP3-DOX nanoparticles has a great potential in facilitating the efficacy of DOX in cancer cells, and the obtained CP3 could be a good candidate as nanocarrier for the encapsulation and delivery of functional compounds.

Bio-responsive Bletilla striata polysaccharide-based micelles for enhancing intracellular docetaxel delivery

The aim of this study was to design a pH- and redox-dual responsive Bletilla striata polysaccharide (BSP)-based copolymer to enhance anti-tumor drugs release at tumor sites and improve the therapeutic effect. The copolymer was synthesized using stearic acid (SA) and cystamine via a disulfide linkage and characterized using 1H-Nuclear Magnetic Resonance spectroscopy and Fourier Transform Infrared spectroscopy. The BSP-ss-SA copolymer could self-assemble into micelle in an aqueous environment and could encapsulate docetaxel therein. Its inhibitory effects on HepG2 cells and 4 T1 cells were determined. Besides, the anti-cancer effects in vivo and histopathological study of 4 T1-bearing tumor mice were also evaluated. Docetaxel-loaded BSP-ss-SA micelles showed significant pH-sensitive release behavior, supplying a greater drug release percentage in pH 5.0 media compared to pH 7.4 media. BSP-ss-SA micelles exhibited a clear redox-responsive release property in pH 7.4 media whereas the similar cumulative release percentage of docetaxel from BSP-ss-SA micelles in pH 5.0 media in the presence and absence of DL-dithiothreitol. The Docetaxel-loaded BSP-ss-SA micelles clearly inhibited the proliferation of HepG2 and 4 T1 cells compared with docetaxel solution. The results of MTT and histopathological study indicated that BSP-ss-SA copolymer exhibited good blood compatibility. The BSP-ss-SA copolymer may be used as carriers to deliver anti-tumor drugs to special tumor tissues.

New cyclodextrin-based supramolecular nanocapsule for codelivery of curcumin and gallic acid

Curcumin, as a naturally occurring polyphenol, has been extensively used as anticancer and antioxidant agent due to its ability to protect cells from oxidative damage. However, its poor solubility and low bioavailability have limited its application. To increase the solubility and effectiveness of curcumin, a new multi-drug delivery system is developed based on curcumin-loaded cyclodextrin-conjugated gallic acid. For this purpose, β-cyclodextrin was grafted by gallic acid, and then, a 2:1 inclusion complex of cyclodextrin and curcumin was prepared. The mean particle size of the curcumin-loaded β-CD-g-GA was about 100 nm by DLS. All observations using FT-IR, NMR, UV–Vis and FE-SEM confirmed successful preparation of the CUR@β-CD-graft-gallic acid. In addition, antioxidant activity and release behavior of the curcumin-loaded β-CD-graft-GA was investigated. The IC50 value for CUR@β-CD-g-GA was estimated (0.4909 µg/mL) based on their inhibition percent–concentration curves using DPPH assay. Also, the total released amount of curcumin within 48 h in pH 7.4 and 5.4 was 41% and 91%, respectively. Because the designed multi-drug delivery system is convenient to prepare, possesses appropriate antioxidant activity and pH-sensitive release behavior and most importantly composed of fully green and safe materials, it may represent an attractive new potent multi-drug delivery system.

Significance of determination of ionized magnesium in acute myocardial infarction

As one of the active pharmaceutical ingredients in Gamboge, Gambogenic acid (GNA) has shown diverse anti-tumor activities. To reduce the vascular irritation of GNA and improve its water solubility, tumor targeting, and bioavailability, GNA loaded Zein nanoparticles ([email protected] NPs) was further coated by polydopamine (PDA) to develop [email protected] NPs by anti-solvent precipitation and surface modification. The results showed that particle size and Zeta potential of [email protected] NPs were about 310 nm and −40.8 mV with core–shell morphology confirmed by TEM. [email protected] NPs increased the water solubility of GNA by more than 700 times and showed pH-sensitive release behavior in PBS with pH 6.86. In vitro cytotoxicity tests showed that [email protected] NPs had higher inhibitory activity on HepG2 cells than free GNA, and their IC50 were 1.59 μg/mL and 9.89 μg/mL, respectively. Additionally, the hemolysis and vascular irritation assay showed that [email protected] NPs had good cytocompatibility and reduced the irritation of GNA to blood vessels. Moreover, the in vivo pharmacokinetic experiments exhibited that the Cmax and AUC0-t of [email protected] NPs were significantly improved approximately by 2.09-fold and 3.48-fold over that of GNA, respectively. In conclusion, [email protected] NPs solve many defects of GNA and provide a tumor-targeting drug delivery for GNA.

The preparation and morphology control of heparin-based pH sensitive polyion complexes and their application as drug carriers

Heparin as negative polysaccharide is a universal building block to form polyion complex with different cationic counterparts. In this paper, three different cations, including chitosan, benzyldodecyldimethyl ammonium bromide and doxorubicin hydrochloride, were used to prepare heparin-based polyion complexes (HPICs). Their morphologies could be tuned by heparin content in HPIC, and they also showed pH-sensitive decomposition. Doxorubicin was further encapsulated into micelle and vesicle carrier made from heparin-benzyldodecyl dimethyl ammonium bromide PIC, whereas heparin-doxorubicin PIC could be directly used as drug carrier. In vitro drug release proved the drug carriers exhibit obvious pH sensitive release behaviour. Cytotoxicity indicated the drug carrier possessed significant cytotoxicity to tumor cells. The cell uptake observed by CLSM showed the carrier was able to deliver antitumor drug into tumor cell’s nucleus. Consequently, these results showed the promising potential of HPIC in drug carrier application.

Preparation and characterization of rod-like chitosan-quinoline nanoparticles as pH-responsive nanocarriers for quercetin delivery.

Novel chitosan-quinoline nanoparticles as anticancer drug nanocarriers were prepared using 2-chloro-3-formylquinoline and 3-formylquinolin-2(1H)-one as non-toxic modifying agents via oil-in-water nanoemulsion technique. Chitosan-quinoline nanoparticles were characterized by FT-IR, UV-vis spectrophotometry, XRD, SEM, AFM and DLS techniques. The morphological and particle size studies demonstrated that drug-loaded chitosan-quinoline nanoparticles have a regular nanorod shape and monolithic structure with the desired particle size of 141 to 174.8 nm and a negative zeta potential of -2.4 to -14.1 mV. Drug loading capacity (LC) and encapsulation efficiency (EE) were achieved using quercetin as a hydrophobic anticancer drug and were about 4.8-9.6% and 65.8-77%, respectively. The in vitro release studies displayed great pH-sensitive release behavior. Evaluation of the anticancer efficacy of quercetin loaded chitosan-quinoline nanoparticles using the in vitro cytotoxicity studies against HeLa cells indicated that the chitosan nanoparticles are a promising candidate for the anticancer drugs delivery.

Microwave induced synthesis of ZnO nanorods and their efficacy as a drug carrier with profound anticancer and antibacterial properties.

In the present study, we report the microwave-induced synthesis of fluorescent zinc oxide nanorods (ZnO) and their usage as a cargo material to carry hydrophobic drug, quercetin. TEM and SEM showed the rod-shape morphology of our synthesized ZnO. XRD showed several diffraction peaks correspond to a hexagonal wurtzite structure. The optical and chemical natures of these nanorods were also confirmed from the UV-vis (showed a distinct absorption bands from 361 to 395 nm) and FTIR spectrum (showed absorption band specific to Zn-O stretching). The synthesized ZnO also showed fluorescence emission at around 550 nm when excited under UV irradiation. Quercetin was loaded onto ZnO surface via employing a metal ion-ligand coordination bond, (ZnO/QR), which exhibit pH-sensitive release behavior. ZnO/QR displayed superior drug loading content (42%) and loading efficiency (72.4%). in vitro assays showed that ZnO/QR exhibited higher anticancer, as well as antibacterial activities compared with free quercetin and ZnO. All these results highlight the synthesis of ZnO nanorods under microwave irradiation, which can be used as a plausible therapeutic option for bioimaging and drug delivery purpose.

A novel pH-sensitive liposome to trigger delivery of afatinib to cancer cells: Impact on lung cancer therapy

A novel drug delivery systems based on cationic (CL) and pH-sensitive liposomes (PSL) for tyrosine kinase inhibitor afatinib (AFT) were developed to enhance tumor-targetability against NSCLC cells and therapeutic effect. Optimal lipid to drug ratio was selected to prepare AFT-loaded PSL and CL with desirable physiochemical properties based on particle size, drug encapsulation efficiency (EE%), stability and release profiles. Moreover, antitumor activity was performed in vitro on human lung cancer cells (H-1975) using a WST-1 assay and Annexin-V apoptosis assay. The mean particle size of the liposomes was <100nm, and EE% was >50% with lipid to drug ratio of 1:0.5. Stability data showed that PSL and CL were physically stable for 1months at 4 and 25°C. In vitro drug release study demonstrated the sustained release of AFT at pH7.5; while PSL exhibited fast drug release in pH5.5. This effect revealed that PSL showed pH-sensitive release behaviors. In addition, the in vitro cytotoxicity study was employed for AFT-loaded PSL due to optimal characterizations. Thus, in vitro anticancer activity revealed that AFT loaded-PSL triggered apoptosis in H-1975 cells. In addition, the inhibitory effect toward H-1975 and HCC-827 was observed, indicating, which indicated high antitumor activity of AFT-loaded PSL. Then, PSL might potentially create practical clinical strategies for better targetability and delivery of AFT for treatment of lung cancer.

Facile synthesis by a covalent binding reaction for pH-responsive drug release of carboxylated chitosan coated hollow mesoporous silica nanoparticles.

In this study, a promising drug nano-carrier system consisting of mono-dispersed and pH sensitive carboxylated chitosan-hollow mesoporous silica nanoparticles (Ccs-HMSNs) suitable for the treatment of malignant cells was synthesised and investigated. At neutral pH, the Ccs molecules are orderly aggregated state, which could effectively hinder the release of loaded drug molecules. However, in slightly acidic environment, Ccs chains are heavily and flexibly entangled in gel state, which would enhance the subsequent controlled release of the loaded drug. Using doxorubicin hydrochloride (DOX•HCl) as the drug model, their results demonstrated that the system had an excellent loading efficiency (64.74 μg/mg Ccs-HMSNs) and exhibited a pH-sensitive release behaviour. Furthermore, confocal laser scanning microscopy revealed that the Ccs-HMSNs nanocomposite could effectively deliver and release DOX•HCl to the nucleus of HeLa cells, thereby inducing apoptosis. In addition, MTT assay also confirmed that DOX•HCl loaded Ccs-HMSNs (DOX•HCl@Ccs-HMSNs) exhibited a good anticancer effect on HeLa cells with a time-dependent manner. Finally, haemolysis experiment showed Ccs-HMSNs had no haemolytic activity at all the tested concentrations (5-320 μg/mL). Thus, this biocompatible and effective nano-carrier system will have potential applications in controllable drug delivery and cancer therapy.

Preparation and characterization of an intelligent multi-target tracking HA-RGD-CLB-QDs drug delivery system

This work aimed to develop an intelligent multi-target tracking hyaluronic acid-RGD-chlorambucil-quantum dots (HA-RGD-CLB-QDs) drug delivery system. After deacetylated, hyaluronic acid was reacted with anticancer drug chlorambucil, RGD, and quantum dots to obtain the HA-RGD-CLB-QDs drug delivery system. The characterization by FT-IR, 1H NMR, TEM, XPS, DLS, and UV-vis absorption and fluorescence spectra show that the system is successfully constructed with an average particle size of about 70 nm. The results of the drug release profile show that that the system has a pH and enzyme sensitive controlled release behaviour. Moreover, cellular uptake and toxicity results show that the system has an ideal dual receptor-mediated endocytosis pathway that significantly enhances the efficacy of CLB tumor therapy and has a lower toxicity to normal cells.The system shows the potential application as a carrier for cancer therapy.

Transferrin-conjugated magnetic dextran-spermine nanoparticles for targeted drug transport across blood-brain barrier.

Application of many vital hydrophilic medicines have been restricted by blood-brain barrier (BBB) for treatment of brain diseases. In this study, a targeted drug delivery system based on dextran-spermine biopolymer was developed for drug transport across BBB. Drug loaded magnetic dextran-spermine nanoparticles (DS-NPs) were prepared via ionic gelation followed by transferrin (Tf) conjugation as targeting moiety. The characteristics of Tf conjugated nanoparticles (TDS-NPs) were analyzed by different methods and their cytotoxicity effects on U87MG cells were tested. The superparamagnetic characteristic of TDS-NPs was verified by vibration simple magnetometer. Capecitabine loaded TDS-NPs exhibited pH-sensitive release behavior with enhanced cytotoxicity against U87MG cells, compared to DS-NPs and free capecitabine. Prussian-blue staining and TEM-imaging showed the significant cellular uptake of TDS-NPs. Furthermore, a remarkable increase of Fe concentrations in brain was observed following their biodistribution and histological studies in vivo, after 1 and 7 days of post-injection. Enhanced drug transport across BBB and pH-triggered cellular uptake of TDS-NPs indicated that these theranostic nanocarriers are promising candidate for the brain malignance treatment. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2851-2864, 2017.

One-step formation of lipid-polyacrylic acid-calcium carbonate nanoparticles for co-delivery of doxorubicin and curcumin

A doxorubicin (Dox) and curcumin (Cur) combination treatment regimen has been widely studied in pre-clinical research. However, the nanoparticles developed for this combination therapy require a consecutive drug loading process because of the different water-solubility of these drugs. This study provides a strategy for the “one-step” formation of nanoparticles encapsulating both Dox and Cur. We took advantage of polyacrylic acid (PAA) and calcium carbonate (CaCO3) to realise a high drug entrapment efficiency (EE) and pH-sensitive drug release using a simplified preparation method. Optimisation of lipid ratios and concentrations of CaCO3 was conducted. Under optimal conditions, the mean diameter of PEGylated lipid/PAA/CaCO3 nanoparticles with encapsulated Cur and Dox (LPCCD) was less than 100 nm. An obvious pH-sensitive release of both drugs was observed, with different Dox and Cur release rates. Successful co-delivery of Cur and Dox was achieved via LPCCD on HepG2 cells. LPCCD altered the bio-distribution of Dox and Cur in vivo and decreased Dox-induced cardiotoxicity. The current investigation has developed an efficient ternary system for co-delivery of Dox and Cur to tumours, using a “one-step” formation resulting in nanoparticles possessing remarkable pH-sensitive drug release behaviour, which may be valuable for further clinical studies and eventual clinical application.

Preparation and properties evaluation of a novel pH-sensitive liposomes based on imidazole-modified cholesterol derivatives

As a new kind of drug carries, pH-sensitive liposomes have been widely studied in tumor therapy for their advantages of target ability and sustained-release. Here, we synthesized a pH-sensitive material, N-(3-Aminopropyl)imidazole-cholesterol (IM-Chol) and prepared a novel pH-sensitive liposomes using IM-Chol and phosphatidylcholine. IM-Chol was synthesized through amidation reaction between the amino group of N-(3-Aminopropyl)imidazole and acyl chloride group of cholesteryl chloroformate in a weak base solution. Optimal conditions to prepare liposomes were obtained by the orthogonal experiment with the higher encapsulation efficiency as the evaluation indicator. The properties of liposomes, such as particle size, zeta potential, morphology, encapsulation efficiency, drug release behavior and in vitro cell toxicity were evaluated by transmission electron microscopy (TEM), dynamic light scattering (DLS) and MTT assay respectively. The results showed that the average particle size of IM-Chol liposomes was 141nm (PDI 0.323). Liposomes can assemble into uniform spheres at pH 7.4, but under the condition of pH 5.0, the spherical structure of IM-Chol liposomes was broken, exhibiting pH-sensitive property. In vitro drug releasing studies demonstrated the controlled-release behavior of the curcumin (CUR) in the IM-Chol liposomes. The cumulative release of CUR reached to 72.5% in the first 24h at pH 5.0, faster than that at pH 7.4, which confirmed that the drug carrier displayed pH-sensitive release behaviors. In addition, the MTT assay was employed to test the cytotoxicity of IM-Chol liposomes and CUR IM-Chol liposomes. All cell viabilities were greater than 80% after incubating for 24h, even up to the highest dose of 500mg/L, indicating that IM-Chol liposomes had good biocompatibility. The tumor inhibitory results towards EC109 cells of free CUR and CUR-loaded IM-Chol liposomes indicated that IM-Chol liposomes indeed enhanced the cell killing effect of CUR. These results showed that the novel IM-Chol liposomes prepared in this paper had pH-sensitive property and were expected to play a huge potential in tumor treatment.

Bone-Targeted Mesoporous Silica Nanocarrier Anchored by Zoledronate for Cancer Bone Metastasis.

Once bone metastasis occurs, the chances of survival and quality of life for cancer patients decrease significantly. With the development of nanomedicine, nanocarriers loading bisphosphonates have been built to prevent cancer metastasis based on their enhanced permeability and retention (EPR) effects; however, as a passive mechanism, the EPR effects cannot apply to the metastatic sites because of their lack of leaky vasculature. In this study, we fabricated 40 nm-sized mesoporous silica nanoparticles (MSNs) anchored by zoledronic acid (ZOL) for targeting bone sites and delivered the antitumor drug doxorubicin (DOX) in a spatiotemporally controlled manner. The DOX loading and release behaviors, bone-targeting ability, cellular uptake and its mechanisms, subcellular localization, cytotoxicity, and the antimigration effect of this drug delivery system (DDS) were investigated. The results indicated that MSNs-ZOL had better bone-targeting ability compared with that of the nontargeted MSNs. The maximum loading capacity of DOX into MSNs and MSNs-ZOL was about 1671 and 1547 mg/g, with a loading efficiency of 83.56 and 77.34%, respectively. DOX@MSNs-ZOL had obvious pH-sensitive DOX release behavior. DOX@MSNs-ZOL entered into cells through an ATP-dependent pathway and then localized in the lysosome to achieve effective intracellular DOX release. The antitumor results indicated that DOX@MSNs-ZOL exhibited the best cytotoxicity against A549 cells and significantly decreased cell migration in vitro. This DDS is promising for the treatment of cancer bone metastasis in the future.

Multifunctional Gd,Ce,Tb co-doped β-tricalcium phosphate porous nanospheres for sustained drug release and bioimaging.

Multifunctional Gd,Ce,Tb co-doped β-tricalcium phosphate (TCP) porous nanospheres are prepared by a facile solvothermal strategy with trimethyl phosphate as the phosphorus source. The as-prepared nanomaterial (average diameter of 100 nm) has a multiple level pore size distribution with the specific surface area of 124.33 m2 g-1, which benefits drug loading. Its photoluminescent and magnetic multifunctions are realized by the co-doping of Gd3+, Ce3+ and Tb3+ ions, which make the nanomaterial promising for both fluorescence and magnetic resonance imaging techniques. Furthermore, the nanomaterial exhibits excellent cytocompatibility and a relatively high doxorubicin loading capacity as well as sustained pH-sensitive drug release behaviour. It is suggested that the Gd,Ce,Tb co-doped β-TCP porous nanospheres are promising for applications in the biomedical fields such as multifunctional drug delivery systems and tissue engineering scaffolds with bioimaging guidance.

PH-Sensitive carboxymethyl chitosan-modified cationic liposomes for sorafenib and siRNA co-delivery

Combination of chemotherapeutic drug and small interfering RNA (siRNA) can affect multiple disease pathways and has been proven effective in suppressing tumor progression. Co-delivery of drug and siRNA within a same nanocarrier is a vital means in this field. The present study aimed at the development of a pH-sensitive liposome to co-deliver drug and siRNA to tumor region. Driven by the electrostatic interaction, the pH-sensitive material, carboxymethyl chitosan (CMCS), was coated onto the surface of the cationic liposome (CL) preloaded with sorafenib (Sf) and siRNA (Si). To evaluate whether the resulting CMCS-modified Sf and siRNA co-delivery cationic liposome (CMCS-SiSf-CL) enhanced antitumor efficiency after systematic administration, in vitro and in vivo experiments were evaluated in HepG2 cells and the H22 cells-bearing Kunming mice model. The experimental results demonstrated that CMCS-SiSf-CL was able to condense siRNA efficiently and protect siRNA from being degraded by serum and RNase. The release rate of Sf from CMCS-modified liposome exhibited pH-sensitive release behavior. Furthermore, in vitro cellular uptake results showed that CMCS-SiSf-CL yielded higher fluorescence intensity at pH 6.5 than at pH 7.4, and that siRNA could be delivered to tumor site by CMCS-SiSf-CL in vivo. The in vivo antitumor efficacy showed that CMCS-Sf-CL inhibits tumor growth effectively when compared with free Sf solution. In current experimental conditions, this liposomal formulation did not show significant toxicity both in vitro and in vivo. Therefore, co-delivering Sf with siRNA by CMCS-SiSf-CL might provide a promising approach for tumor therapy.

Synthesis and Characterization of pH-Responsive Copolypeptides Vesicles for siRNA and Chemotherapeutic Drug Co-Delivery.

Novel diblock copolypeptides are synthesized and evaluated as a pH-sensitive drug delivery vector for anticancer drugs and siRNA co-delivery. The synthetic process involve the ring opening polymerization of α-amino acid N-carboxyanhydrides as well as aminolysis and deprotection reactions, and the structures are characterized. The copolypeptides can self-assemble into stable vesicles at neutral pH, and disassemble in acidic endosomal/lysosomal, which shown the pH-responsive behavior. The cell uptake results indicated that the vesicles can co-deliver DOX and siRNA inside the same cell and exhibit a pH-sensitive release behavior. Therefore, the novel polymeric vesicles are a promising carrier for co-delivery anticancer drug and siRNA to overcome the drug resistance and enhance cancer treatment.