pH-sensitive Drug Delivery System Research Articles

Oxime Linkage: A Robust Tool for the Design of pH-Sensitive Polymeric Drug Carriers

Oxime bonds dispersed in the backbones of the synthetic polymers, while young in the current spectrum of the biomedical application, are rapidly extending into their own niche. In the present work, oxime linkages were confirmed to be a robust tool for the design of pH-sensitive polymeric drug delivery systems. The triblock copolymer (PEG-OPCL-PEG) consisting of hydrophilic poly(ethylene glycol) (PEG) and hydrophobic oxime-tethered polycaprolactone (OPCL) was successfully prepared by aminooxy terminals of OPCL ligating with aldehyde-terminated PEG (PEG-CHO). Owing to its amphiphilic architecture, PEG-OPCL-PEG self-assembled into the micelles in aqueous media, validated by the measurement of critical micelle concentration (CMC). The MTT assay showed that PEG-OPCL-PEG exhibited low cytotoxicity against NIH/3T3 normal cells. Doxorubicin (DOX) as a model drug was encapsulated into the PEG-OPCL-PEG micelles. Drug release study revealed that the DOX release from micelles was significantly accelerated at mildly acid pH of 5.0 compared to physiological pH of 7.4, suggesting the pH-responsive feature of the drug delivery systems with oxime linkages. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements indicated that these DOX-loaded micelles were easily internalized by living cells. MTT assay against HeLa cancer cells showed DOX-loaded PEG-OPCL-PEG micelles had a high anticancer efficacy. All of these results demonstrate that these polymeric micelles self-assembled from oxime-tethered block copolymers are promising carriers for the pH-triggered intracellular delivery of hydrophobic anticancer drugs.

PH-Sensitive Poly(Vinyl Alcohol)/Sodium Carboxymethylcellulose Hydrogel Beads for Drug Delivery

A series of pH-sensitive hydrogel beads were prepared composed of poly(vinyl alcohol) (PVA) and sodium carboxymethylcellulose (CMC) by using Fe3+ crosslinking and freeze-thawing (FT) cycle techniques. The mixed solution of CMC and PVA was firstly crosslinked with Fe3+ to form beads and then subjected to freezing-thawing cycles for further crosslinking. The formation of hydrogel was confirmed by Fourier transform infrared spectroscopy (FTIR). The gelling rate in ferric solution and the swelling and pH-senstive properties of the hydrogel beads were investigated. The encapsulation efficiency and in-vitro release properties of beads were also evaluated using Bovine serum albumin as model drug. The pH sensitivity and the release rate increased with increasing CMC content. These results suggest that the PVA/CMC hgdrogel beads should be useful as pH-sensitive drug delivery systems for bioactive agents.

PH-Triggered Controlled Drug Release from Mesoporous Silica Nanoparticles via Intracelluar Dissolution of ZnO Nanolids

Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity.

A pH-sensitive polymeric nanovesicle based on biodegradable poly(ethylene glycol)-b-poly(2-(diisopropylamino)ethyl aspartate) as a MRI-visible drug delivery system

Diblock copolymers of poly(ethylene glycol) (PEG) and biodegradable 2-(diisopropylamino)ethanol grafted poly(L-aspartic acid) (PAsp(DIP)) were synthesized and evaluated as a MRI-visible and pH-sensitive drug delivery system. The copolymers can self-assemble into stable vesicles in aqueous solutions at neutral pH, resembling the physiological environment, whereas they disassemble in acidic endosomal/lysosomal compartments of tumor cells to achieve rapid drug release. The anticancer drug doxorubicin (DOX) and hydrophilic superparamagnetic iron oxide nanoparticles (SPIONs) were encapsulated inside the inner aqueous core of the vesicles for cancer therapy and MR imaging, respectively. In vitrodrug release studies showed that the DOX release from the pH-sensitive vesicles was significantly faster at pH 5.0 than at pH 7.4. SPIONs clustering inside the inner aqueous core of the vesicles resulted in a high spin–spin (T2) relaxivity. Cell culture studies showed that the DOX-SPION-loaded vesicles could be effectively internalized by human hepatic cancer Bel 7402 cells, and DOX could be rapidly released from vesicles inside lysosomal compartments and then migrated into nuclei. Consequently effective suppression of cancer cell growth was detected. This study demonstrated the potential of the biodegradable DOX-SPION-loaded pH-sensitive vesicles as an effective multifunctional nanomedicine platform for cancer therapy due to their pH-triggerable drug release and high MRI sensitivity.

Synthesis of starch-g-poly(acrylic acid-co-2-hydroxy ethyl methacrylate) as a potential pH-sensitive hydrogel-based drug delivery system

The present work focused on the design of a drug delivery system (DDS) based on pH-sensitive hydrogel. The hydrogels were prepared via graft copolymerization of mixtures of acrylic acid (AA) and 2-hydroxy ethyl methacrylate (HEMA) onto starch backbones by a free radical polymerization technique. Sodium bicarbonate (NaHCO3) was added to function as a foaming agent under acidic conditions, rendering the hydrogels to be porous. The porous structure of the hydrogel was essential in this system to yield a large surface area so that 5-fluorouracil (5-FU) release could be facilitated. The hydrogel, thus prepared, possessed a porous structure as determined by scanning electron microscopy. The water absorbency of the hydrogels was measured in solutions with pH levels ranging from 1 to 13. The starch-based hydrogel exhibited a pH-responsiveness character such that a swelling-deswelling pulsatile behavior was recorded at pH levels of 2 and 7. Using the drug 5-FU as a model molecule, the in vitro controlled drug-release behaviors of these hydrogels were investigated. The results indicate that the main parameter affecting the drug-release behavior of hydrogels is the pH of the solution. The release rate of 5-FU from hydrogel at pH 7.4 was faster than that at pH 1.2 due to the shrinkage of the hydrogel at pH 1.2. These results suggest that a porous hydrogel could potentially be a useful local delivery system to release drugs, primarily at a specific site of body.

Design and Mechanism of On–Off Pulsed Drug Release Using Nonenteric Polymeric Systems via pH Modulation

The aim was to design a pH-sensitive pulsatile drug delivery system that allows for an on-off pulsed release of a drug using polyacrylic acid (PAA) blended with ethyl cellulose (EC) in different ratios. PAA, a polyelectrolyte polymer, exhibits a highly coiled conformation at low pH but a highly extended structure at high pH. Fumaric acid, which is an internal acidifying agent, was incorporated into the hydroxypropyl methylcellulose-based core tablets to create an acidic microenvironmental pH (pH(M)). The concentration of fumaric acid inside the core tablet and the ratio of PAA/EC in the coating layer were very crucial in modulating drug release behaviors. When the fumaric acid was retained in the core tablet, it gave a more acidic pH(M), so that the PAA was kept in a highly coiled state in the coated film, which hindered drug release ("off" release pattern). Interestingly, the release profiles of the drug and fumaric acid from coated tablets showed the on-off pulsed pattern upon dissolution. Imaging analyses using scanning electron microscopy, near-infrared imaging, confocal laser scanning microscopy, and Fourier transform infrared spectroscopy confirmed this on-off release behavior of the drug and fumaric acid from coated tablets.

Core/Shell Nanoparticles for pH-Sensitive Delivery of Doxorubicin

Core/shell nanoparticles with lipid core were prepared and characterized as pH-sensitive delivery system of anticancer drug. The lipid core is composed of drug-loaded lecithin and the polymeric shell is composed of Pluronics (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) tri-block copolymer, F-127). Based on the preparation method in the previous report by us, the freeze-drying of drug-loaded lecithin was performed in the F-127 aqueous solution containing trehalose used as a cryoprotectant to form stabilized core/shell nanoparticles. For the application of core/shell nanoparticles as a pH-sensitive drug delivery system for anticancer drug, doxorubicin was loaded into the core/shell nanoparticles and the drug loading amount and drug release behavior in response to pH change were observed.

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.

In Vitro Release Behavior of Naproxen in Alginate–Chitosan Microparticles as Oral Drug Delivery Systems

Due to its topical irritant effect on gastric mucosa naproxen is an ideal candidate for encapsulation in pH sensitive drug delivery systems such as alginate– chitosan microparticles. [...]

PH sensitive alginate-chitosan hydrogel beads for carvedilol delivery

Alginate-chitosan hydrogel beads for carvedilol delivery were prepared to be used as a controlled pH-sensitive drug delivery system. The beads were characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The swelling ability and in vitro release of carvedilol in solutions of different pH value were investigated. They exhibited significant swelling rates when exposed to the slightly alkaline environment. The results suggest that the system has potential to be used as an effective pH-controlled delivery system for carvedilol. The release of carvedilol at various pH values was analyzed by a semi-empirical equation.

Preparation and Characterization of Superporous Hydrogels as pH-Sensitive Drug Delivery System for Pantoprazole Sodium

The objective of the present study is to develop Superporous Hydrogel (SPH) and SPH composites (SPHC) as pH-sensitive drug delivery system for Pantaprazole sodium. In this investigation, Superporous hydrogels containing poly(methacrylic acid-co-acrylamide) with interconnected pores of several hundreds of micrometer were prepared using radical polymerization of methacrylic acid and acrylamide in the presence of N,N-methylene-bis-acrylamide as crosslinking agent. A gas blowing method using bicarbonate as a foaming agent was applied to introduce the porous structure. SPH composite polymers were made in the same way, except for using Ac-Di-Sol as a stabilizer. The structures of the SPH and SPH composites were characterized by FT-IR and Scanning electron microscopy (SEM). Apparent density and swelling ratio studies were also carried out. The swelling properties and mechanical strength of SPHs were affected by the addition of the mechanical stabilizer, Ac-Di-Sol. Results indicated that SPH polymers have more pores and higher swelling ratio but less mechanical stability compared to SPH composite polymers, which have less pores and lower swelling ratio but a higher mechanical stability. With a change in pH from acidic to basic, a considerable increase in swelling was observed for all the formulations. Since the prepared SPH and SPHC swell only in the basic pH, it may be concluded that SPH and SPHC can be used as pH-sensitive drug delivery systems for Pantoprazole sodium.

A novel thermosensitive polymer with pH-dependent degradation for drug delivery

A class of thermosensitive biodegradable multiblock copolymers with acid-labile acetal linkages were synthesized from Pluronic ® triblock copolymers (Pluronic ® P85 and P104) and di-(ethylene glycol) divinyl ether. The novel polymers were engineered to form thermogels at body temperature and degrade in an acidic environment. The Pluronic ®-based acid-labile polymers were characterized using nuclear magnetic resonance, gel permeation chromatography and differential scanning calorimetry. In vitro biocompatibility of the synthesized polymers was evaluated using calorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. The polymers showed reverse thermogelling behavior in water around body temperature. The sol–gel transition temperatures of the polymers synthesized from Pluronic ® P85 and P104 were lowered from 70.3 to 30 °C and from 68.5 to 26.9 °C, respectively, when the synthesized polymers were compared with corresponding Pluronic ® block copolymers at a concentration of 25 wt.%. The hydrophobic dye solubilization confirmed the formation of polymeric micelles in the aqueous solution. The sizes of the multiblock copolymers increased on a rise in temperature, indicating that thermal gelation was mediated by micellar aggregation. The thermally driven hydrogels showed preferential polymer degradation at acidic pH. At pH 5.0 and 6.5, the release of 40 kDa fluorescein isothiocyanate–dextran (FITC–dextran) from the thermally formed hydrogels was completed within 2 and 9 days, respectively. However, FITC–dextran was continuously released up to 30 days at neutral pH. The mechanism of FITC–dextran release at pH 5.0 was mainly an acid-catalyzed degradation, whereas both diffusion and pH-dependent degradation resulted in FITC–dextran release at pH 6.5. The novel polymers hold great potential as a pH-sensitive controlled drug delivery system owing to their interesting phase transition behavior and biocompatibility.

A pH‐sensitive nano drug delivery system derived from pullulan/doxorubicin conjugate

A novel pH-sensitive nanoparticle drug delivery system for doxorubicin (DOX) is prepared. Pullulan, a natural biocompatible polysaccharide, was partly carboxymethylized; hydrazine hydrate was condensed with the carboxyl groups forming hydrazide. The hydrazide was coupled with DOX through the formation of hydrazone bond. The chemical structure of the conjugate was determined by FTIR and (1)H NMR. The pullulan/DOX conjugate nanoparticles were formed through the aggregation of hydrophobic DOX. The size and morphology of prepared nanoparticles were characterized using dynamic light scattering and transmission electron microscope. The results showed that the nanoparticles were spherical and their size was less than 100 nm. The content of DOX in conjugate was 3.18 wt %. The investigation of the release behavior in vitro indicated that the DOX was released from nanoparticles faster at pH 5.0 (62% DOX released within 24 h) than at pH 7.4 (29% DOX released within 24 h). The in vitro cytotoxicity of pullulan/DOX conjugate nanoparticles was tested by the MTT assay.

PH-sensitive polymers for cytoplasmic drug delivery

The pH-sensitive drug delivery systems could be triggered by a mild acidic environment, such as that occurring in solid tumors, inflammatory tissues and intracellular endosomal compartments. Moreover, the cytoplasmic delivery of internalized macromolecules (such as oligonucleic acid, siRNA, DNA, proteins and polymer–antibody complex) will be possible. Synthetic polymers – such as polyanions (acrylic acid derivatives) and polycations (poly ethylenimine and chitosan complexes) – are among the most popular compounds studied for intracellular trafficking of drugs. As research is progressing in the area of cytoplasmic delivery, many novel and innovative applications making use of the unique properties of pH-sensitive polymers are expected in the future.

NOVEL pH-SENSITIVE DRUG DELIVERY SYSTEM BASED ON NATURAL POLYSACCHARIDE FOR DOXORUBICIN RELEASE

A novel pH-sensitive nanoparticle drug delivery system (DDS) derived from natural polysaccharide pullulan for doxorubicin (DOX) release was prepared. Pullulan was functionalized by successive carboxymethylization and amidation to introduce hydrazide groups. DOX was then grafted onto pullulan backbone through the pH-sensitive hydrazone bond to form a pullulan/DOX conjugate. This conjugate self-assembled to form nano-sized particles in aqueous solution as a result of the hydrophobic interaction of the DOX. Transmission electron microscope (TEM) and dynamic light scattering (DLS) characterization showed that the nanoparticles were spherical and their size was less than 100 nm. The DOX released from the nanoparticles in a pH-sensitive manner. In vitro cytotoxicity assay indicated the pullulan/DOX nanoparticles showed comparable cytotoxicity effect with free DOX on the 4T1 mouse breast cancer cells.

Novel dexamethasone-HPMA copolymer conjugate and its potential application in treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease of unknown etiology. Effective treatment of this disorder has been hampered by the lack of availability of agents that selectively target affected joint tissue. We developed a novel pH-sensitive drug delivery system of dexamethasone (Dex) based on an N-(2-hydroxypropyl)methacrylamide copolymer (P-Dex) and have shown that the delivery system specifically accumulates in inflamed joints in an animal model of arthritis. We hypothesize that the arthrotropism of the delivery system and the local acidosis-mediated drug release provide superior therapeutic efficacy and potentially reduced side effects in RA treatment. The initial in vitro drug-release study confirmed that the Dex release is indeed dependent upon the environmental pH. At pH 5, 37°C, the conjugate shows the highest level of drug release. When administered systemically in an adjuvant-induced arthritis rat model, P-Dex offers superior and longer-lasting anti-inflammatory effects compared with systemically administered free Dex. In addition, greater bone and cartilage preservation was observed with the P-Dex treatment compared with free Dex treatment. Our data indicate that the differential effect of the conjugate is related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release (extracellular and intracellular) in arthritic joints. This newly developed drug delivery system provides a unique method for selective targeting of glucocorticoids to inflamed joints which may potentially reduce systemic side effects.

Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model

The objective of this study was to evaluate the anti-tumor efficacy and lack of systemic toxicity of paclitaxel when administered in pH-sensitive poly(ethylene oxide) (PEO)-modified poly(beta-amino ester) (PbAE) nanoparticles in mice bearing human ovarian adenocarcinoma (SKOV-3) xenograft. Paclitaxel-encapsulated PEO-modified PbAE (PEO-PbAE) nanoparticles were prepared by the solvent displacement method. PEO-modified poly(epsilon-caprolactone) (PCL) (PEO-PCL) nanoparticles were used as a non pH-responsive control formulation. Efficacy studies were conducted in SKOV-3 tumor-bearing athymic (Nu/Nu) mice at an equivalent paclitaxel dose of 20 mg/kg with the control and nanoparticle formulations. Safety of the drug when administered in the control and nanoparticle formulation was determined from blood cell counts and changes in body weight of the animals. The formulated paclitaxel-containing PEO-PbAE and PEO-PCL nanoparticles had a particle size in the range of 100-200 nm and a surface charge of + 39.0 and - 30.8 mV, respectively. After intravenous administration of paclitaxel in these formulations, the tumor growth was inhibited significantly. Both of the formulated nanoparticles tested have shown improved therapeutic efficacy as compared to the paclitaxel aqueous solution. Additionally, significantly lower toxicity profile of paclitaxel was observed with PEO-modified nanoparticles as compared to the aqueous solution formulation PEO-modified PbAE nanoparticles are a unique pH-sensitive drug delivery system that elicits enhanced efficacy and safety profile in solid tumor therapy.

Development of carboxymethyl cellulose acrylate for various biomedical applications

The purpose of this work is to prepare a pH-sensitive hydrogel membrane of sodium carboxymethyl cellulose acrylate for drug delivery and other biomedical applications. The hydrogel was made by esterification of sodium carboxymethyl cellulose (SCMC) and acryloyl chloride (ACl). The esterified product was characterized by FTIR spectroscopy and XRD. Swelling, hemocompatibility, water vapor transmission rate, contact angle and diffusional studies were also done. Biocompatibility of the membrane was established by quantification of cell growth of L929 cells and mice splenocytes. The FTIR spectrum of the hydrogel suggested the formation of ester bonds between the hydroxyl groups of sodium carboxymethyl cellulose and the carbonyl group of acryloyl chloride. Water vapor transmission rate, hemocompatibility, contact angle and swelling studies indicated that the hydrogel can be tried as a wound dressing material. The hydrogel showed pH-dependent swelling behavior arising from the acidic pendant group in the polymer network. The permeability of the hydrogel membrane produced, as shown by salicylic acid diffusion, increased in response to an increase in pH of the external medium. The hydrogel membrane was permeable to salicylic acid at pH 7.2 but not at pH 2.0 (0.01N HCl). The effect of changes of pH on the hydrogel's permeability was found to be reversible. The hydrogel membrane was found to be compatible with the L929 mice fibroblast cell line and mice splenocytes. The esterified product of SCMC and ACl swells on increase of pH indicating its possible use in a pH-sensitive drug delivery system and as a wound dressing material.

PH-sensitive hydrogel based on a polyaspartamide derivative

A pH-sensitive hydrogel was prepared by UV irradiation technique. Starting polymer was obtained from α,β-poly (N-2-hydroxyethyl)-DL-aspartamide (PHEA) partially derivatized with glycidyl methacrylate (PHG). The PHG copolymer was cross-linked by UV irradiation in the presence of methacrylic acid (MA) to form a pH sensitive hydrogel. The cross-linked matrix shaped as microparticles was characterized by FT-IR spectrophotometry, XPS, X-ray diffraction, SEM and particle size distribution analyses. Moreover, to have information about water affinity of the prepared sample, swelling measurements were carried out in aqueous media mimicking some biological fluids. In order to employ the prepared network as a pH-sensitive drug delivery system, propionyl-L-carnitine, chosen as a model drug, was entrapped into this hydrogel both during the irradiation process and after cross-linking reaction by a soaking technique. In vitro release studies showed that the drug release rate depends on the different swelling of the network as a function of the environmental pH as well as on the different drug loading method.

PH-sensitive microparticles for oral drug delivery

This article shall give an overview on pH-sensitive microparticulate drug delivery systems with a main focus on their application in oral drug administration. It deals with the major therapeutic strategies to which such microparticles can be applied mainly based on the selective drug delivery towards specific areas in the gastrointestinal tract. Beside taste masking pH-sensitive microparticles have been used for the avoidance of gastric irritation. Most of the approaches described in literature however, aim for the increase of bioavailability of the entrapped drug. For the increase of oral bioavailability of fragile drugs, such as peptides or proteins, pH-sensitive microparticles are intended to protect the entrapped drug load against its degradation in the upper intestinal tract and to deliver it in a more advantageous environment. In a similar way, microparticles have proved their efficiency for oral vaccination. In addition to the above mentioned delivery strategies targeting the most promising absorption site, other therapeutic approaches aim for selective local drug delivery, especially for applications in inflammatory bowel disease. This overview of the different applications of pH-sensitive microparticles for oral administration emphasizes their versatility and underlines that they may be an interesting tool in order to open new therapeutic pathways for a large diversity of diseases.