pH-triggered Drug Delivery Research Articles

A pH-responsive emulsion stabilized by alginate-grafted anisotropic silica and its application in the controlled release of λ-cyhalothrin

Alginate (Alg) was grafted on the surface of anisotropic silica (SiO2-x) via the Ugi reaction (Alg-SiO2-1, Alg-SiO2-2, and Alg-SiO2-4). Compared with pristine SiO2-x, modified SiO2-x is more sensitive to pH. Three stable liquid paraffin-in-water emulsions were prepared with Alg-SiO2-1, Alg-SiO2-2, and Alg-SiO2-4. Alg-SiO2-2 exhibited satisfactory emulsification ability. The emulsions became more stable as emulsion pH varied from 2.0 to 6.2 because of polymer chain interactions that led to the formation of a three-dimensional network. When the emulsion pH varied from 6.2 to 8.0, the particle charge increased, in turn increasing interparticle the electrostatic interactions that increased emulsion stability. When the emulsion pH was 9.0, the subsequent decrease in particle charge, decreased the emulsion stability. The model drug λ-cyhalothrin was embedded in the emulsions. A sustained-release assay demonstrated that increasing emulsion pH from 3.0 to 8.0 decreased cumulative drug release from the emulsion from 99.7% to 13.5%. This result indicated that the emulsion is a pH triggered drug delivery system. The sustained-release curves of λ-cyhalothrin are describable by the Weibull model.

PH-responsive poly (acrylic acid)-gated mesoporous silica and its application in oral colon targeted drug delivery for doxorubicin

Oral chemotherapy is the preferred route for cancer treatment because it can improve the efficacy and decrease the side effects. Unfortunately, most anticancer drugs suffered from their poor oral bioavailability. Herein, we construct a novel pH-triggered oral drug delivery system by capping of mesoporous silica SBA-15 with pH-responsive polymer poly (acrylic acid) (PAA) via a facile graft-onto strategy. The experiment results demonstrated that the PAA brushes were anchored on the pore outlets of mesoporous silica SBA-15, which can be acted as the gatekeeper to control the drug molecules transport in and out of the pore channels. The PAA capped mesoporous SBA-15 (PAA/SBA-15) exhibited a high drug loading capacity (785.7mg/g), excellent pH-sensitivity and good biocompatibility. In gastric environment (pH=2.0), the drug doxorubicin (DOX) molecules were encapsulated in the pore channels because the pore outlets were capped with collapsed PAA. In contrast, in colonic environment (pH=7.6), it exhibited a fast release because of the removal of capping. In addition, the water solubility of DOX in colonic environment was enhanced after DOX being loaded into the pores of PAA/SBA-15. This pH-triggered oral drug delivery system has promising applications for treatment of colon cancer and other colon diseases.

A ‘grafting from’ approach to polymer nanorods for pH-triggered intracellular drug delivery

We report the use of the ‘grafting from’ approach to produce inherently rod-shaped polymer nanoparticles with triggered drug release. Cylindrical polymer brushes (CPBs) can be directly used to yield functional polymer nanorods for pH-sensitive drug release of doxorubicin (DOX). Water-soluble CPBs have been produced via a straightforward one-step grafting of vinyl benzaldehyde (VBA) and poly(ethylene glycol) methyl ether methacrylate (PEGMA) comonomers, in which the VBA distributed throughout the CPBs provides a cost-effective and simple functionality for the subsequent conjugation of DOX using imine chemistry. Atomic force microscopy (AFM) underlined the rod-like conformation of the CPBs prior and after drug conjugation. Fluorescence spectroscopy studies revealed faster drug release in acidic environments (pH 5.0) compared to physiological pH conditions (pH 7.4). Fluorescence lifetime imaging microscopy (FLIM) and in vitro cell studies further highlighted the intracellular DOX release from the CPB drug carriers within MCF-7 breast cancer cells.

Graphene oxide and adenosine triphosphate as a source for functionalized carbon dots with applications in pH-triggered drug delivery and cell imaging

A folate-functionalized carbon dot-based nanocarrier system has been successfully synthesized for cancer cell targeted drug delivery.

Core–shell structured nanospheres for photothermal ablation and pH-triggered drug delivery toward synergistic cancer therapy

Core–shell CuS(DOX)@CS nanospheres with pH-responsive drug release ability and photothermal conversion properties are synthesized for synergistic cancer therapy.

Theranostic hyaluronic acid prodrug micelles with aggregation-induced emission characteristics for targeted drug delivery

Theranostic hyaluronic acid (HA) prodrug micelles with pH-responsive drug release and aggregation-induced emission (AIE) properties were prepared by chemical graft of biomimetic phosphorylcholine (PC), anticancer drug doxorubicin (DOX) and AIE fluorogen tetraphenylene (TPE) to the HA backbone. DOX was conjugated to the HA backbone by a hydrazone bond which can be hydrolyzed under acidic environment and result in pH-triggered smart release of DOX. The TPE units with typical AIE characteristics were applied for real time drug tracking in cancer cells. The HA-based prodrugs could self-assemble into micelles in aqueous solution as confirmed by the dynamic light scattering (DLS) and transmission electron microscopy (TEM). The intracellular distribution of HA prodrug micelles could be clearly observed by fluorescence microscopy based on the strong fluorescence of TPE. Moreover, after treated with the micelles, stronger fluorescence of TPE in CD44 overexpressed MDA-MB-231 cancer cells was observed, compared to the CD44 negative cell line, NIH3T3 cells, suggesting efficient cell uptake of HA prodrug micelles by receptor-mediated endocytosis. The cell viability results indicated that the prodrug micelles could inhibit the proliferation of the cancer cells effectively. Such pH-triggered theranostic drug delivery system with AIE features can provide a new platform for targeted and image-guided cancer therapy.

PH-Triggered Sustained Drug Delivery from a Polymer Micelle having the β-Thiopropionate Linkage.

The synthesis, micellar aggregation, and pH-triggered intracellular drug delivery ability of an amphiphilic statistical copolymer (P2) are studied. Two methacrylate derivatives, one containing a hydrophilic pendant and the other containing a hydrophobic pendant chain, are copolymerized to produce P2. The hydrophobic pendant chain is linked to the polymer backbone by a β-thiopropionate linkage, known to undergo slow hydrolysis at mild acidic pH. P2 forms a multimicellar cluster in water with a critical aggregation concentration of 0.02 mg mL(-1) and encapsulates a hydrophobic guest such as pyrene, Nile red, or the anti-cancer drug doxorubicin (Dox). Sustained release of the entrapped Dox (80% after 100 h) is noticed at pH 5.2, while release is significantly slower (35% after 100 h) at pH 7.4. Acidic hydrolysis of the β-thiopropionate linkage leading to the reduction of the hydrophobicity is established as the cause for micellar disassembly and triggered drug release. Cell-culture studies with the human breast cancer cell line, MCF-7, reveal biocompatibility of P2 (below 150 μg mL(-1) ). It is further tested for intracellular delivery of Dox. MCF-7 cells remain healthy at pH 7.4 but become unhealthy at pH 5.2 when treated with a Dox-loaded P2 micelles.

Facile incorporation of dispersed fluorescent carbon nanodots into mesoporous silica nanosphere for pH-triggered drug delivery and imaging

Dispersed incorporation of functional nanoparticles into ordered mesopores to exert their synergistic properties has shown a promising application, but proved to be a challenging task. Herein, a facile strategy based on solid-phase transformation of the template into polymer-coated carbonaceous nanodots (pCNDs) is used for direct synthesis of multifunctional mesoporous silica nanospheres (MFMSNs) incorporated with dispersed fluorescent carbon nanodots. The homogeneous pCNDs incorporated into mesoporous silica nanospheres (MSNs) can simultaneously act as the nontoxic fluorescence probe for highly efficient fluorescence imaging and also anchoring sites for anticancer drug loading. On the basis of the special hydrophobic π–π/electrostatic interaction between the confined pCNDs in MFMSNs and the aromatic drug molecules, MFMSNs could also function as an advanced drug carrier for pH-triggered drug release. The very simple strategy suggests new insights for synthesizing multifunctional mesoporous nanomaterials and extends the biomedical functions of traditional MSN-based nanovehicles for future biomedical applications.

Can a catanionic surfactant mixture act as a drug delivery vehicle?

Surfactants can self-assemble in dilute aqueous solutions into a variety of microstructures, including micelles, vesicles, and bilayers. Recently, there has been an increasing interest in unilamellar vesicles, which are composed of a closed bilayer that separates an inner aqueous compartment from the outer aqueous environment. This interest is motivated by their potential to be applied as vehicles for active agents in drug delivery via several routes of administration. Active drug molecules can be encapsulated in the bilayer membrane if they are lipophilic or in the core of the vesicle if they are hydrophilic. Furthermore vesicles formed by mixing of cationic and anionic surfactants (so called ‘catanionic’ systems) can be used as models for biological membranes as they have low critical micelle concentration ( cmc ) and are highly biocompatible. In this work the formation of amino acid based mixed surfactant vesicles and their stabilization and biocompatibility were studied systematically using several instrumental techniques. Binary mixtures of the anionic sodium N -alkanoyl- l -sarcosinate, SAS and cationic cetyltrimethylammonium hydroxide (CTAOH) or dodecyltrimethylammonium hydroxide (DTAOH) surfactant was found to form high surface active and strong synergistic interaction in different compositions and concentrations. • Mixture of cationic and anionic surfactants (i.e., catanionic mixture) forms stable vesicles. • The vesicles can be used for pH-triggered drug delivery. • The vesicles can entrap the drug molecules to their inner aqueous core. • The catanionic vesicles are biocompatible in nature.

Responsive nanogels for application as smart carriers in endocytic pH-triggered drug delivery systems

Various specially designed poly(N-isopropylacrylamide-co-acrylic acid) (NIPA-co-AAc) nanogels (NGs) with different NIPA/AAc molar composition were synthesized by precipitation/dispersion polymerization and evaluated as carriers for drug delivery systems (DDSs) of doxorubicin hydrochloride (DOXO·HCl) for cancer therapies. The NGs presented excellent dispersability in physiological environments (pH 7.4 and 5 at 37°C), as shown by dynamic light scattering (DLS). Moreover, the NGs exhibited high drug loading capacity and efficiency due to the ionic interaction of the cationic drug with the anionic NGs. NG-DOXO·HCl formulation presented excellent dispersability in water and minimal leakage of the cargo at plasma simulated medium (pH 7.4 and 0.14M NaCl) at 37°C and a triggered release at lysosomal simulated medium (pH 5 and 0.14M NaCl). This release behavior together with their size and the low cytotoxicity determined by the MTT assay converts these NGs in great candidates for their application as carriers in cancer therapies based on the enhanced permeability and retention effect (EPR) with drug pH-triggered release after endocytosis in tumor cells.

Injectable hydrogels by inclusion complexation between a three-armed star copolymer (mPEG-acetal-PCL-acetal-)3 and α-cyclodextrin for pH-triggered drug delivery

Novel acid-cleavable and injectable supramolecular hydrogels based on inclusion complexes between the acid-cleavable star copolymer (mPEG-a-PCL-a-)3 and α-CD were prepared, and used as controlled drug delivery depots.

A self-assembled DNA nanostructure for targeted and pH-triggered drug delivery to combat doxorubicin resistance.

We developed a novel self-assembled DNA nanostructure for anticancer drug delivery. The resulting nanostructure was able to specifically target cancer cells and release the loaded drug at pH 5.0. More importantly, the drug-loaded DNA nanostructure effectively circumvented doxorubicin resistance of human lung adenocarcinoma epithelial cancer cells.

Evaluation of novel antiproliferative controlled drug delivery system based on poly(2-hydroxypropyl acrylate/itaconic acid) hydrogels and nickel complex with Oxaprozin

A series of dual-sensitive poly(2-hydroxypropyl acrylate/itaconic acid) (P(HPA/IA)) hydrogels were synthesized and evaluated as potential highly effective antiproliferative drug delivery system. Investigated hydrophobic antiproliferative agent, Ni(II) complex with Oxaprozin, was successfully synthesized and efficiently loaded into the’”intelligent” P(HPA/IA) hydrogels. Swelling studies showed that loaded agent did not annul pH- and temperature-sensitivity of the investigated hydrogels. In vitro antiproliferative activity of investigated complex against human cervical (HeLa) and melanoma cancer (FemX) cell lines was tested. The results of in vitro release study at different pH values confirmed synthesized hydrogels loaded with investigated complex as a highly effective pH-triggered drug delivery system for the advanced anticancer therapy as well as for the targeted treatment of intestine/colon cancers.

Poly(maleic acid-co-propane-1,2-diol-co-adipic acid) for pH-triggered drug delivery

Poly(maleic acid-co-propane-1,2-diol-co-adipic acid) was synthesized using xylene as the reaction medium in Dean–Stark apparatus. The synthesized co-polyester was characterized by its FTIR-spectrum, elemental analysis, molecular weights, solubility in common organic solvents and hydrolytic degradation test. From the hydrolytic degradation study it was found that the polyester sample remained almost intact in the acid medium but gradually degraded in basic medium. Because of such pH-responsive degradation nature, this polyester was tried as an enteric coating material for non-steroidal anti-inflammatory drugs. Drug release from the polymer coated specimen in simulated physiological environments was investigated and British Pharmacopoeia standard enteric coating properties of the polymer were observed.

Folate-conjugated biodegradable core cross-linked polyphosphoester micelles for targeted and pH-triggered drug delivery

Folate-conjugated biodegradable core cross-linked polyphosphoester micelles for targeted and pH-triggered drug delivery

Selective intracellular drug delivery from pH-responsive polyion complex micelle for enhanced malignancy suppression in vivo

The pH-triggered intracellular drug delivery platforms have attracted great interest in malignancy therapy. Herein, a pH-responsive polyion complex (PIC) micelle from anionic acid-sensitive methoxy poly(ethylene glycol)-block-poly(N(ϵ)-((1-carboxy-cis-cyclohexene)-2-carbonyl)-L-lysine) (mPEG-b-PCLL) and cationic doxorubicin (DOX), a model anthracycline antitumor drug, was constructed by electrostatic interaction for directional intracellular drug delivery in malignancy chemotherapy. The PIC micelle kept constant diameter at physiological condition (i.e., pH 7.4), while gradually swelled and finally disassembled at mimicking intratumoral pH (i.e., 6.8) and especially intracellular endo/lysosomal pH (i.e., 5.5). The DOX release from the PIC micelle at pH 7.4 was slow, whereas obviously accelerated at the intracellular acidic condition of pH 5.5. These results should be related to the rapid cleavage of the side amide bond of mPEG-b-PCLL in an acidic environment. The PIC micelle exhibited satisfactory tumor suppression toward the H22 hepatoma-bearing BALB/c mouse model compared with free DOX, which was demonstrated by the upregulated tumor inhibition rate, and the increased necrotic and apoptosis areas in tumor tissue. Furthermore, the enhanced security was also observed in the PIC micelle group in relation to that of free DOX. The above results strongly supported that the acid-sensitive PIC micelle was promising for selective intracellular drug delivery along with upregulated malignancy inhibition.

Evaluation of poly(hydroxyethyl acrylate/itaconic acid) hydrogels for controlled delivery of transition metal complexes with Oxaprozin as potential antiproliferative agents

A series of dual-sensitive poly(2-hydroxyethyl acrylate/itaconic acid) (P(HEA/IA)) hydrogels were synthesized and evaluated as drug delivery systems for potential antiproliferative agents. Investigated hydrophobic compounds, Mn(II) and Zn(II) complexes with Oxaprozin, were efficiently loaded into the P(HEA/IA) hydrogels, which was confirmed by FTIR and UV–Vis spectroscopy. Swelling studies, conducted in the physiological pH range of 2.20–8.00 and in temperature range of 30–50 °C, demonstrated that loaded transition metal complexes in P(HEA/IA) hydrogels did not annul pH and temperature sensitivity of the hydrogels. In vitro antiproliferative activity of Mn(II) and Zn(II) complexes with Oxaprozin against human cervical (HeLa) and melanoma cancer (Fem X) cell lines was tested. Results of in vitro release study investigated at different pH conditions confirmed P(HEA/IA) hydrogels as a highly effective pH-triggered drug delivery system for hydrophobic antiproliferative agents. These performances indicate that P(HEA/IA) hydrogels loaded with transition metal complexes can be further studied as a promising candidate for anticancer therapy, as well as for targeted treatment of intestine/colon cancers.

Doxorubicin-conjugated β-NaYF4:Gd(3+)/Tb(3+) multifunctional, phosphor nanorods: a multi-modal, luminescent, magnetic probe for simultaneous optical and magnetic resonance imaging and an excellent pH-triggered anti-cancer drug delivery nanovehicle.

Herein, we report the fabrication of a multifunctional nanoprobe based on highly monodispersed, optically and magnetically active, biocompatible, PEI-functionalized, highly crystalline β-NaYF4:Gd(3+)/Tb(3+) nanorods as an excellent multi-modal optical/magnetic imaging tool and a pH-triggered intracellular drug delivery nanovehicle. The static and dynamic photoluminescence spectroscopy showed the presence of sharp emission peaks, with long lifetimes (∼3.5 milliseconds), suitable for optical imaging. The static magnetic susceptibility measurements at room temperature showed a strong paramagnetic signal (χ∼ 3.8 × 10(-5) emu g(-1) Oe(-1)). The nuclear magnetic resonance (NMR) measurements showed fair T1 relaxivity (r1 = 1.14 s(-1) mM(-1)) and magnetic resonance imaging gave enhanced T1-weighted MRI images with increased concentrations of β-NaYF4:Gd(3+)/Tb(3+) making them suitable for simultaneous magnetic resonance imaging. In addition, an anticancer drug, doxorubicin (DOX) was conjugated to the amine-functionalized β-NaYF4:Gd(3+)/Tb(3+) nanorods via pH-sensitive hydrazone bond linkages enabling them as a pH-triggered, site-specific drug delivery nanovehicle for DOX release inside tumor cells. A comparison between in vitro DOX release studies undertaken in normal physiological (pH 7.4) and acidic (pH 5.0) environments showed an enhanced DOX dissociation (∼80%) at pH 5.0. The multifunctional material was also applied as an optical probe to confirm the conjugation of DOX and to monitor DOX release via a fluorescence resonance energy transfer (FRET) mechanism. The DOX-conjugated β-NaYF4:Gd(3+)/Tb(3+) nanorods exhibited a cytotoxic effect on MCF-7 breast cancer cells and their uptake by MCF-7 cells was demonstrated using confocal laser scanning microscopy and flow cytometry. The comparative cellular uptakes of free DOX and DOX-conjugated β-NaYF4:Gd(3+)/Tb(3+) nanorods were studied in tumor microenvironment conditions (pH 6.5) using confocal imaging, which showed an increased uptake of DOX-conjugated β-NaYF4:Gd(3+)/Tb(3+) nanorods. Thus, DOX-conjugated β-NaYF4:Gd(3+)/Tb(3+) nanorods combining pH-triggered drug delivery, efficient luminescence and paramagnetic properties are promising for a potential multifunctional platform for cancer therapy, biodetection, and optical and magnetic resonance imaging.

Core cross-linked polyphosphoester micelles with folate-targeted and acid-cleavable features for pH-triggered drug delivery

Novel folate-conjugated acid-cleavable core cross-linked polyphosphoester micelles have been prepared and used for pH and enzyme-triggered delivery of doxorubicin.

Precise modular synthesis and a structure–property study of acid-cleavable star-block copolymers for pH-triggered drug delivery

A series of well-defined three-armed star-block copolymers (mPEG-a-PCL-a-)3 linked with acid-cleavable acetal groups have been prepared and used for the pH-triggered delivery of doxorubicin.