pH-responsive Drug Release System Research Articles

Combining emulsion electrospinning with surface functionalization to fabricate multistructural PLA/CS@ZIF-8 nanofiber membranes toward pH-responsive dual drug delivery

Developing of the multifunctional polymeric carrier for controlled drug release is still one of most challenging task. In this work, a pH-responsive dual drug delivery system was designed and prepared based on the zeolitic imidazolate framework-8 (ZIF-8). The poly(lactic acid)/chitosan (PLA/CS) core-shell nanofiber membranes by emulsion electrospinning, which the hydrophilic drug (Astragalus Polysacharin, APS) was encapsulated in the CS core and the hydrophobic drug (Camptothecin, CPT) was loaded into the PLA shell, respectively. Subsequently, ZIF-8 nanoparticles served as the protective layer were immobilized on the surface of PLA/CS to form multi-structural PLA/CS@ZIF-8 nanofiber membranes. In vitro drug release of nanofiber membranes were studied in the acidic and neutral medium, respectively. The results were that the hydrophilicity and surface roughness of nanofiber membranes rose with increasing of 2-MIM concentrations. The nanofiber membranes also had excellent pH-responsive and controlled release property. Furthermore, the drug release of PLA/CS@ZIF-8 for either APS or CPT were all carried out in a coexisting manner of diffusion and skeleton corrosion. In addition, in vitro cytotoxicity assay indicated nanofiber membranes with good cytocompatibility. Therefore, the multi-structured PLA/CS@ZIF-8 nanofiber membranes has been used as a potential pH-responsive dual drug release system.

Design and Characterisation of pH-Responsive Photosensitiser-Loaded Nano-Transfersomes for Enhanced Photodynamic Therapy.

Photodynamic therapy (PDT) is a non-invasive and tumour-specific therapy. Photosensitizers (PSs) (essential ingredients in PDT) aggregate easily owing to their lipophilic properties. The aim of this study was to synthesise a PS (methyl pheophorbide a, MPa) and design a biocompatible lipid-based nanocarrier to improve its bioavailability and pharmacological effects. MPa-loaded nano-transfersomes were fabricated by sonication. The characteristics of synthesised PS and nano-transfersomes were assessed. The effects of PDT were evaluated by 1,3-diphenylisobenzofuran assay and by measuring photo-cytotoxicity against HeLa and A549 cell lines. The mean particle size and zeta potential for nano-transfersomes ranged from 95.84 to 267.53 nm and −19.53 to −45.08 mV, respectively. Nano-transfersomes exhibited sustained drug release for 48 h in a physiological environment (as against burst release in an acidic environment), which enables its use as a pH-responsive drug release system in PDT with enhanced photodynamic activity and reduced side effects. The formulations showed light cytotoxicity, but no dark toxicity, which meant that light irradiation resulted in anti-cancer effects. Additionally, formulations with the smallest size exhibited photodynamic activity to a larger extent than those with the highest loading capacity or free MPa. These results suggest that our MPa-loaded nano-transfersome system is a promising anti-cancer strategy for PDT.

Design of a pH-responsive oral gel formulation based on the matrix systems of gelatin/hydroxypropyl methylcellulose phthalate for controlled drug release

Extensive efforts have been directed toward developing novel easily digested formulations with desirable controlled-release properties. The present study sought to develop pH-responsive oral gel formulations using combinations of gelatin and enteric polymers for controlled drug release under stimulated gastric conditions using acetaminophen and fluorescein isothiocyanate (FITC)-labeled dextran as model compounds. Hydroxypropyl methylcellulose phthalate (HPMCP) was identified as the optimal excipient for the pH-responsive drug release system because the release rates of acetaminophen in gelatin/HPMCP gels at pH 1.2 were exceedingly lower than those in other polymer-containing gels. Texture profile analysis of gelatin/HPMCP gels revealed the optimal content of excipients concerning ingestibility. FITC-labeled dextran of varying molecular weights was used to investigate the mechanism of compound release from the gelatin/HPMCP system under acidic conditions. The release properties practically depended on the molecular weight of FITC-dextran, and the compound release rate was proportional to the square root of time. The matrix structures of gelatin/HPMCP gels at low pH offer advantageous pH-responsive drug release profiles.

Combinatory Cancer Therapeutics with Nanoceria-Capped Mesoporous Silica Nanocarriers through pH-triggered Drug Release and Redox Activity

In the field of nanomedicine, drug-loaded nanocarriers that integrate nanotechnology and chemotherapeutics are widely used to achieve synergistic therapeutic effects. Here, we prepared mesoporous silica nanoparticles capped with cerium oxide nanoparticles (COP@MSN) wherein a pH trigger-responsive mechanism was used to control drug release and intracellular drug delivery. We blocked the mesopores of the carboxyl-functionalized MSN with aminated COP. These pores could be opened in acidic conditions to release the loaded drug, thus establishing a pH-responsive drug release system. We loaded doxorubicin (DOX) as anticancer biomolecule into the pores of MSN and capped with COP. The COP@DOX-MSN system showed a typical drug release profile in an acidic medium, which, however, was not observed in a neutral medium. In vitro studies using cancer cell line (HeLa) proved that the COP@DOX-MSN entered efficiently into HeLa cells and released DOX to the level sufficient for cytotoxicity. The cytotoxic effect of COP in cancer cells was facilitated by the pro-oxidant property of COPs, which considerably raised the reactive oxygen species (ROS) level, thereby leading to cellular apoptosis. The combination of DOX with COP (COP@DOX-MSN) showed even higher ROS level, demonstrating a cytotoxic synergism of drug and nanoparticle in terms of ROS generation. Collectively, the COP@DOX-MSN is considered useful for cancer treatment with the combined capacity of pH-controlled drug delivery, chemotherapeutics, and redox activity.

Designing pH-Responsive Biodegradable Polymer Coatings for Controlled Drug Release via Vapor-Based Route.

We present the design of a novel pH-responsive drug release system that is achieved by solventless encapsulation of drugs within a microporous membrane using a thin capping layer of biodegradable poly(methacrylic anhydride) (PMAH) coating. The coating was synthesized via a mild vapor polymerization process, namely, initiated chemical vapor deposition, which allowed perfect retention of the anhydride groups during deposition. The synthesized polyanhydride underwent degradation upon exposure to aqueous buffers, resulting in soluble poly(methacrylic acid). The degradation behavior of PMAH is highly pH-dependent, and the degradation rate under pH 10 is 15 times faster than that under pH 1. The release profile of a model drug rifampicin clearly exhibited two stages: the initial stage when the coatings were being degraded but the drugs were well stored and the second stage when drugs were gradually exposed to the medium and released. The drug release also showed strong pH responsiveness where the duration of the initial stage under pH 1 was more than 7 and 3 times longer than that under pH 10 and 7.4, respectively, and the release rates at pH 7.4 and 10 were significantly faster than that at pH 1. The pH-dependent degradation of the encapsulant thus enabled good preservation of drugs under low-pH environment but high drug release efficiency under neutral and alkaline environment, suggesting potential applications in site-specific drug delivery systems.

PH-Responsive fluorescent dye-labeled metal-chelating polymer with embedded cadmium telluride quantum dots for controlled drug release of doxorubicin

This paper describes the synthesis and characterization of a pH-responsive drug release system based on cadmium telluride quantum dots capped by fluorescent dye-labeled poly (N-(2-(2-amino-ethylamino)-ethyl methacrylamide) metal-chelating polymer. Fluorescent dye is a model for an active molecule which shows our polymer can be attached to bioactive agents such as antibody or a functional drug. Furthermore, it indicates the success of ligand exchange between anchor groups on polymer surface and QDs. The polymer was synthesized using reversible addition fragmentation chain transfer polymerization, resulting in polymers with controllable molecular weights and low polydispersities. The use of diethylenetriamine allows obtaining hydrophilic polymers with amine functional groups available for conjugation with QDs. Furthermore, the amine moieties of the polymer guarantee the pH sensitivity of the system. The obtained nano carrier was monodispersed with very small diameter around 4.5 nm which confirmed by TEM. The obtained nanoparticles show low cytotoxicity in cell viability studies. The release rates of doxorubicin (DOX) anticancer drug conjugates were studied at pH 5.4 and pH 7.4. The release behavior for DOX in pH 7.4 (pH of normal cells) is <1%, while it is high at pH 5.4 (pH of cancer cells).

PH-responsive nanoreservoirs based on hyaluronic acid end-capped mesoporous silica nanoparticles for targeted drug delivery

Mesoporous silica nanoparticles (MSNs) are greatly appealing for efficient drug delivery due to their excellent drug loading capacities. However, it remains as a major challenge to realize site-specific controlled release with MSNs. This work examines a smart pH-responsive drug release system using MSNs for CD44-targeting drug delivery. Specifically, hyaluronic acid (HA) was applied as an end-capping agent to seal drug loads inside the mesoporous of MSNs through the acid labile hydrazine bonds. HA exposed on the surface of the particles can also serve as a targeting agent at the same time, enable site specific targeting toward CD-44 overexpressing cells. The system showed a good stability at physiological pHs, yet drug release could be triggered in response to changes in pH. Further studies showed that the HA-fabricated particles could achieve much enhanced cellular uptake via CD44 receptor-mediated endocytosis by Hela cells (CD44 receptor-positive), and as a result, doxorubicin-loaded MSNs exhibited significantly enhanced drug efficacy toward cancer cells overexpressing CD44 receptor (IC50 = 0.56 μg/mL), whereas the normal cells showed weakly cytotoxicity (IC50 = 1.03 μg/mL). Such a fabrication strategy may provide a new platform for preparation of high performance drug delivery systems for cancer therapy.

PH-responsive drug release system of Cu2+-modified ammoniated TiO2 nanotube arrays

The pH-responsiveness has been one of the focuses in the controlled drug release, in which coordination complexes are used to store and release drugs through the formation and cleavage of coordination bonds, respectively. In this work, polylysine-modified TiO2 nanotubes and alendronate drug, which contain amino groups, were used to coordinate Cu2+ ions and form “amino-metal-drug” coordination system. The system showed pH-responsive release of the drug. At a low pH or acidic condition, these coordination bonds were unstable and could be easily disrupted. However, increase of pH caused the bonds to become more strengthen so that the drug could not be released easily. We demonstrated that this coordination system not only increased drug loading, but also reduced drug release rate, which was found to reduce by 52 wt% in a buffer of pH = 7.4.

Preparation of poly(styrene-alt-maleic anhydride) grafted multi-walled carbon nanotubes for pH-responsive release of doxorubicin

ABSTRACTA pH-responsive drug release system based on doxorubicin conjugated poly(styrene-alt-maleic anhydride) grafted multi-walled carbon nanotubes (MWNT/PSMA-DOX) was prepared by the reversible addition-fragmentation chain transfer (RAFT) polymerization and acid-cleavable hydrazone linkages. Firstly, multi-walled carbon nanotubes (MWNTs) were modified with a furfuryl derivative RAFT agent by Diels-Alder reaction. The polymerization of styrene and maleic anhydride was carried out in the presence of functionalized MWNTs to afford MWNT/PSMA. The maleic anhydride ring located along the polymer chains was opened by hydrazine subsequently conjugated with doxorubicin via an acid-sensitive hydrazone bond. The composite materials were characterized by FT-IR, 1H-NMR, TGA and TEM analysis. In vitro experiments showed a burst release of doxorubicin at pH 5.0 whereas slight release at pH 7.4.

Synthesis of dual-functional targeting probes for cancer theranostics based on iron oxide nanoparticles coated by centipede-like polymer connected with pH-responsive anticancer drug

A tumor-targeted and pH-responsive drug release system based on superparamagnetic iron oxide nanoparticles (IONPs) coated by poly(ethylene glycol) (PEG) and dodecylamine (DDA)-modified polyitaconic acid (PIA) connecting with bortezomib (BTZ) (PIA-PEG-DDA-BTZ@IOs) has been constructed and characterized. The anticancer drug BTZ was first conjugated using dopamine as the linker via catechol borate ester bond, which is acid cleavable and used as an ideal pH-responsive drug release system. The IONPs were then coated by PIA-PEG-DDA-BTZ to form micelles with good biocompatibility. The conjugates were further designed to target liver cancer cells overexpressing vascular endothelial growth factor (VEGF) by the targeting molecule anti-vascular endothelial growth factor (anti-VEGF). The magnetic resonance imaging showed that the targeting capability of IONPs-anti-VEGF conjugates to Hep G2 cells was more significant than that of non-anti-VEGF IONPs. From the above, this kind of novel dual-functional targeting probe could provide a new idea for the diagnosis and treatment of cancer.

Synthesis and characterization of DOX-conjugated dendrimer-modified magnetic iron oxide conjugates for magnetic resonance imaging, targeting, and drug delivery

A tumor targeted and pH-responsive drug release system that is based on folic acid (FA) conjugated to poly(ethylene glycol) (PEG)-modified dendrimers (PAMAM) with doxorubicin (DOX) and superparamagnetic iron oxide (Fe3O4) (FA-PEG-PAMAM-DOX@IONPs) has been constructed and characterized. IONPs were stabilized by FA-PEG-G3.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which are acid cleavable and can be used as an ideal pH-responsive drug release system. The PEG moiety attached to the PAMAM@IONPs provides the conjugates with excellent solubility and stability in an aqueous medium, which may increase the circulation time. The attached FA could target the conjugates to the folate receptor (FR). These novel DOX-loaded conjugates have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering drugs to the target sites.

Novel water-soluble and pH-responsive anticancer drug nanocarriers: Doxorubicin–PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs)

PH-responsive drug release system based on the conjugates of PAMAM dendrimers–doxorubicin (PAMAM–DOX) and superparamagnetic iron oxide (Fe 3O 4) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH-responsive drug release system. The drug release profiles of DOX–PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH = 5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer–DOX-coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo.