pH-responsive Drug Delivery System Research Articles

Synthesis, characterization, and evaluation of the anticancer properties of pH-responsive carvacrol-zinc oxide quantum dots on breast cancer cell line (MDA-MB-231).

Since most solid tumors have a low pH value, a pH-responsive drug delivery system may offer a broad method for tumor-targeting treatment. The present study is used to analyze the anticancer activity of carvacrol-zinc oxide quantum dots (CVC-ZnO QDs) against breast cancer cells (MDA-MB-231). CVC-ZnO QDs demonstrate pH responsive and are specifically released within the acidic pH tumor microenvironment. This property enables targeted drug delivery exclusively to cancer cells while minimizing the impact on normal cells. To the synthesized ZnO QDs, the CVC was loaded and then examined by X-ray diffraction, ultraviolet-visible, Fourier transform infrared spectrophotometer, scanning electron microscopy-energy dispersive X-ray, and transmission electron microscopy. For up to 20 h, CVC release was examined in different pH-buffered solutions. The results showed that carvacrol release was stable in an acidic pH solution. Further, cytotoxicity assay, antioxidant, and lipid peroxidation activity, reactive oxygen species, mitochondrial membrane potential, nuclear damage, and the ability of CVC-ZnO QDs to cause apoptosis were all examined. Apoptosis markers such as Bcl2, Bax, caspase-3, and caspase-9, were also studied. In conclusion, the CVC-ZnO QDs destabilized the MDA-MB-231cells under its acidic tumor microenvironment and regulated apoptosis.

Assembled pH-Responsive Gastric Drug Delivery Systems Based on 3D-Printed Shells

Assembled pH-Responsive Gastric Drug Delivery Systems Based on 3D-Printed Shells

Development of pH-responsive Eudragit S100-functionalized silk fibroin nanoparticles as a prospective drug delivery system.

Silk fibroin nanoparticles (FNP) have been increasingly investigated in biomedical fields due to their biocompatibility and biodegradability properties. To widen the FNP versatility and applications, and to control the drug release from the FNP, this study developed the Eudragit S100-functionalized FNP (ES100-FNP) as a pH-responsive drug delivery system, by two distinct methods of co-condensation and adsorption, employing the zwitterionic furosemide as a model drug. The particles were characterized by sizes and zeta potentials (DLS method), morphology (electron microscopy), drug entrapment efficiency and release profiles (UV-Vis spectroscopy), and chemical structures (FT-IR, XRD, and DSC). The ES100-FNP possessed nano-sizes of ∼200-350 nm, zeta potentials of ∼ -20 mV, silk-II structures, enhanced thermo-stability, non-cytotoxic to the erythrocytes, and drug entrapment efficiencies of 30%-60%, dependent on the formulation processes. Interestingly, the co-condensation method yielded the smooth spherical particles, whereas the adsorption method resulted in durian-shaped ones due to furosemide re-crystallization. The ES100-FNP adsorbed furosemide via physical adsorption, followed Langmuir model and pseudo-second-order kinetics. In the simulated oral condition, the particles could protect the drug in the stomach (pH 1.2), and gradually released the drug in the intestine (pH 6.8). Remarkably, in different pH conditions of 6.8, 9.5, and 12, the ES100-FNP could control the furosemide release rates depending on the formulation methods. The ES100-FNP made by the co-condensation method was mainly controlled by the swelling and corrosion process of ES100, and followed the Korsmeyer-Peppas non-Fickian transport mechanism. Whereas, the ES100-FNP made by the adsorption method showed constant release rates, followed the zero-order kinetics, due to the gradual furosemide dissolution in the media. Conclusively, the ES100-FNP demonstrated high versatility as a pH-responsive drug delivery system for biomedical applications.

Antiepileptic drug-loaded and multifunctional iron oxide@silica@gelatin nanoparticles for acid-triggered drug delivery

The current study developed an innovative design for the production of smart multifunctional core-double shell superparamagnetic nanoparticles (NPs) with a focus on the development of a pH-responsive drug delivery system tailored for the controlled release of Phenytoin, accompanied by real-time monitoring capabilities. In this regard, the ultra-small superparamagnetic iron oxide@silica NPs (IO@Si MNPs) were synthesized and then coated with a layer of gelatin containing Phenytoin as an antiepileptic drug. The precise saturation magnetization value for the resultant NPs was established at 26 emu g-1. The polymeric shell showed a pH-sensitive behavior with the capacity to regulate the release of encapsulated drug under neutral pH conditions, simultaneously, releasing more amount of the drug in a simulated tumorous-epileptic acidic condition. The NPs showed an average size of 41.04 nm, which is in the desired size range facilitating entry through the blood–brain barrier. The values of drug loading and encapsulation efficiency were determined to be 2.01 and 10.05%, respectively. Moreover, kinetic studies revealed a Fickian diffusion process of Phenytoin release, and diffusional exponent values based on the Korsmeyer-Peppas equation were achieved at pH 7.4 and pH 6.3. The synthesized NPs did not show any cytotoxicity. Consequently, this new design offers a faster release of PHT at the site of a tumor in response to a change in pH, which is essential to prevent epileptic attacks.

Expression of Concern: pH-Responsive Anticancer Drug Delivery Systems: Insights into the Enhanced Adsorption and Release of DOX Drugs using Graphene Oxide as a Nanocarrier

Expression of Concern: pH-Responsive Anticancer Drug Delivery Systems: Insights into the Enhanced Adsorption and Release of DOX Drugs using Graphene Oxide as a Nanocarrier

Innovative chitosan-polyacrylic acid-MoS2 nanocomposite for enhanced and pH-responsive quercetin delivery

Cancer remains a global health challenge, with current treatments often leading to adverse side effects. Herein, a pH-sensitive, biocompatible nanocomposite composed of chitosan (CS), polyacrylic acid (PAA), and MoS2 nanosheets, loaded with quercetin (QCT) as a model anticancer drug has been synthesized via the water-oil-water (W/O/W) emulsification method, with the aim to be used for targeted breast cancer treatment. Characterization via Fourier-transform infrared spectroscopy (FT-IR) revealed strong interaction between the polymers via hydrogen bonding, and X-ray diffraction (XRD) showed a reduction in the level of crystallinity upon drug loading. Dynamic light scattering (DLS), zeta potential, and field-emission scanning electron microscopy (FE-SEM) tests revealed that the synthesized nanocarriers were spherical in shape and had a hollow structure, with a mean size of 484 nm and a high zeta potential of +44.3 mV, which confirms their high colloidal stability. The addition of MoS2 nanosheets to the polymeric mixture increased drug loading and encapsulation efficiency to 47% and 89%, respectively. The nanocomposite showed high potential as a pH-responsive drug delivery system, releasing 97% and 68% of QCT in acidic and neutral environments, respectively, over 96 hours. The biological performance was investigated using MTT and flow cytometry assays, which confirmed the efficiency of the nanocomposite for tumor cell removal.

A Remarkable Impact of pH on the Thermo-Responsive Properties of Alginate-Based Composite Hydrogels Incorporating P2VP-PEO Micellar Nanoparticles.

A heterograft copolymer with an alginate backbone, hetero-grafted by polymer pendant chains displaying different lower critical solution temperatures (LCSTs), combined with a pH-responsive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) diblock copolymer forming micellar nanoparticles, was investigated in aqueous media at various pHs. Due to its thermo-responsive side chains, the copolymer forms hydrogels with a thermo-induced sol-gel transition, above a critical temperature, Tgel (thermo-thickening). However, by lowering the pH of the medium in an acidic regime, a remarkable increase in the elasticity of the formulation was observed. This effect was more pronounced in low temperatures (below Tgel), suggesting secondary physical crosslinking, which induces significant changes in the hydrogel thermo-responsiveness, transforming the sol-gel transition to soft gel-strong gel. Moreover, the onset of thermo-thickening shifted to lower temperatures followed by the broadening of the transition zone, implying intermolecular interactions between the uncharged alginate backbone with the PNIPAM side chains, likely through H-bonding. The shear-thinning behavior of the soft gel in low temperatures provides injectability, which allows potential applications for 3D printing. Furthermore, the heterograft copolymer/nanoparticles composite hydrogel, encapsulating a model hydrophobic drug in the hydrophobic cores of the nanoparticles, was evaluated as a pH-responsive drug delivery system. The presented tunable drug delivery system might be useful for biomedical potential applications.

Synthesis, characterization and evaluation of a pH-responsive molecular imprinted polymer for Matrine as an intelligent drug delivery system

Abstract To address the undesirable reactions associated with matrine (MAT) injection in clinical settings, a high-loading drug delivery system (DDS) based on pH-sensitive molecularly imprinted polymer (MAT@MIPs) was prepared for the first time. The imprinted materials containing recognition sites for the matrine were formed by using carboxyl-functionalized multiwalled carbon nanotubes as a supportive matrix and dopamine as a cross-linker due to its exceptional biocompatibility. Subsequently, the optimal reaction conditions and adsorption performance of MAT@MIPs were systematically investigated. The obtained polymers were characterized and evaluated by Fourier transform infrared spectrometry, scanning electron microscopy, elemental analysis, and thermogravimetric analysis. Results indicated that the MIPs demonstrated a favorable imprinting factor (2.36) and a high binding capacity (21.48 mg·g−1) for matrine. In vitro studies, we performed cell counting kit-8 assays in HepG2 cells, then the drug delivery capabilities of MAT-loaded MIPs were validated through light microscopy analyses, and the matrine content in culture medium was quantified using ultra high-performance liquid chromatography-mass spectrum synchronously. The facile fabrication of MAT@MIPs presents a viable solution for designing high-loading and pH-responsive DDS, which can offer a novel administration approach for drugs requiring injection in clinical applications.

Low fouling and pH-responsive poly(N-vinyl imidazole)/poly(ethylene glycol) methacrylate copolymer gels for colon targeted diclofenac sodium delivery

Protein and cell adhesion onto drug delivery matrices interferes with the predesigned drug delivery profile to the targeted site. Antifouling surfaces are needed to overcome this problem and improve the effectiveness and efficiency of drug delivery systems. Copolymers of N-vinyl imidazole (NVI) with poly(ethylene glycol methacrylate) (PEGMA) were synthesized via free radical polymerization under cryogenic conditions as potential pH-responsive drug delivery systems resistant to protein and cell adhesion. FTIR spectroscopy, elemental analysis, thermal analysis (DSC), mechanical tests, contact angle, surface energy, and SEM analysis provide the physicochemical properties of the samples. Static adsorption/adhesion experiments show that the copolymer cryogels resist BSA adhesion. Furthermore, the copolymer cryogels demonstrate anti-cell adhesion behavior against colon colorectal carcinoma (HCT-116) cells. They are non-cytotoxic toward HDFa fibroblasts. Diclofenac sodium (DS) - loaded copolymer cryogels show pH-dependent sustained drug delivery. The release studies show a limited release in stomach pH (2.0). On the other hand, enhanced release is observed in pH 5.0 and pH 7.4 within 15 h. The quantities of diclofenac sodium released from the copolymer cryogels are sufficient to show anti-inflammatory activity.

Zinc-doped hydroxyapatite as a pH responsive drug delivery system for anticancer drug 6-mercaptopurine.

6-Mercaptopurine (6MP) is commonly used in the treatment of acute lymphoblastic leukemia as an important agent in maintenance therapy. Despite its therapeutic benefits, 6MP has some limitations during therapy. Taking into account the disadvantages during 6MP therapy, there is a great need to create an appropriate delivery system for this drug. 6MP contains in its structure nitrogen and sulfur atoms capable of forming coordination compounds with metal ions, for example zinc. Therefore, in this work, we prepared biocompatible hydroxyapatite (HAp) doped with zinc ions, and used it as a carrier for 6MP. Doped HAp has not been used as a carrier for this drug before. The work proved that the prepared carrier-drug system has a particle size of about 130 nm, which indicates its potential for intravenous delivery. In addition, in an acidic environment (imitating cancer cells), the carrier agglomerates allow targeted release of the drug. The drug is evenly distributed, which indicates that the doses released from it will always be comparable. The release of the drug in a neutral environment is long-lasting in controlled doses, whereas in an acidic environment it is immediate. The obtained results indicate the high potential of the material in both slow-release and cancer-targeted release of 6MP.

Rhizobial oxidized 3-hydroxylbutanoyl glycan-based gelatin hydrogels with enhanced physiochemical properties for pH-responsive drug delivery

Rhizobial exopolysaccharide (EPS) is an acidic polysaccharide involved in nitrogen fixation-related signal transduction in the rhizosphere, serving as a structural support for biofilms, and protecting against various external environmental stresses. Rhizobial EPS as a hydrogel biomaterial was used for a pH-responsive drug delivery system combing with gelatins. Pure gelatin (GA) hydrogels have limited practical applications due to their poor mechanical strength and poor thermal stability. We developed new GA hydrogels using oxidized 3-hydroxylbutanoyl glycan (OHbG) as a polymer cross-linking agent to overcome these limitations. OHbG was synthesized from sodium periodate oxidation of 3-hydroxylbutanoyl glycan directly isolated from Rhizobium leguminosarum bv. viciae VF39. The newly fabricated OHbG/GA hydrogels exhibited 21-fold higher compressive stress and 4.7-fold higher storage modulus (G') than GA at the same strain. This result suggested that OHbG provided mechanical improvement. In addition, these OHbG/GA hydrogels showed effective pH-controlled drug release for 5-fluorouracil, self-healable, and self-antioxidant capacity by uronic acids of OHbG. Cell viability tests using HEK-293 cells in vitro also showed that the OHbG/GA hydrogels were non-toxic. This suggests that the new OHbG/GA hydrogels can be used as a potentially novel biomaterial for drug delivery based on its self-healing ability, antioxidant capacity, and pH-responsive drug delivery.

Supramolecular Hydrophobic Eutectogels Based on Menthol-Thymol as Thermo- and pH-Responsive Drug Delivery Systems

Supramolecular Hydrophobic Eutectogels Based on Menthol-Thymol as Thermo- and pH-Responsive Drug Delivery Systems

PVA/guanidinium oleate transdermal patch as a pH-responsive drug delivery system for the localized and targeted delivery of anticancer drugs

pH-responsive Transdermal Patch for the Treatment of Cancer.

Ph-Responsive Drug Delivery System Based on Polymeric Prodrug for Efficient Antitumor Therapy

Ph-responsive micellar nanoparticles in nuclear endosomes were prepared by self-assembling amphiphilic poly (ethylene glycol)-Schiff-doxorubicin (PEG-Schiff-DOX, PSD) predrugs. Self-assembly of an amphiphilic poly (ethylene glycol)-Schiff-doxorubicin (PEG-Schiff-DOX, PSD) prodrug was adopted to prepare endosomal pH-responsive micellar nanoparticles, and the encapsulation of free DOX could be made in the hydrophobic core of the nanoparticles by Schiff base bond. These nanoparticles showed great storage steadiness for above 1 week under normal circumstances but disassembled rapidly to answer faintly acidic environment. Thus, we are able to obtain a simple nano-polymer prodrug material that enables efficient and accurate delivery of tumor drugs and can maintain stability in neutral environments and rapidly degrade in the acidic context of tumor cells. In addition, it benefits from the good stability of PSD with high drug loading concentration and long drug release behavior. According to CCK-8 assays, the nanoparticle showed great antitumor activity over free DOX against HeLa tumor cells. These prodrug-based nanomedicines show excellent potential for the development of translational DOX formulations for cancer therapy.

Novel carboxymethyl cellulose/polyvinyl pyrrolidone hydrogel incorporating graphitic carbon nitride for quercetin delivery

Herein, quercetin (QC) as a model anticancer drug was encapsulated in a carboxymethyl cellulose/polyvinyl pyrrolidone/graphitic carbon nitride (g-C3N4) nanocomposite synthesized via dual oil-in-water emulsification method. The nanocomposite hydrogel showed a high surface area, nano-porous structure and a hydroxylated surface. g-C3N4 enhanced the drug loading efficiency up to 95 %. X-ray diffraction (XRD) and Fourier-transform infrared spectroscopy (FT-IR) analyses provided information about the crystalline structure of the nanocarrier and the interactions between its components, respectively. Field-emission scanning electron microscopy (FESEM) showed its spherical shape, with a mean particle size of 160 nm. Dynamic light scattering (DLS) revealed a monomodal and narrow particle distribution, with a PDI value of 0.12. Further, the average zeta potential was −38.7 mV, indicative of its high colloidal stability. The release kinetics of the drug-loaded nanocomposite was investigated at pH = 5.4 and 7.4, and the results showed a controlled and pH-sensitive release, with 97 % and 54 % QC released after 96 h, respectively. The mechanism of drug release was investigated via fitting the experimental release data to different kinetic models, and the best fitting were obtained for Korsmeyer–Peppas and Baker at pH 7.4 and 5.4, respectively. Significant cytotoxicity of the Qc-loaded nanocomposite on breast cancer model cells, MCF-7, was corroborated by flow cytometry and MTT assays. In addition, improved apoptotic cell death was attained due to the presence of g-C3N4 nanoparticles. Results support the high potential of the developed nanocomposite as a novel pH-responsive drug delivery system for cancer therapy.

Delivery of paclitaxel by carboxymethyl chitosan-functionalized dendritic fibrous nano-silica: Fabrication, characterization, controlled release performance and pharmacokinetics

In this study, carboxymethyl chitosan (CMCS) with excellent biocompatibility was used as the “gatekeeper” to design and fabricate a pH-responsive drug delivery system (CMCS-DFNS) as paclitaxel carriers. Characterization results showed that CMCS-DFNS was successfully prepared and the nanocarriers displayed excellent drug loading efficiency of 19.8 %, and the results of the adsorption mechanism revealed that the adsorption of PTX was consistent with the Freundlich isotherm and pseudo-second-order kinetic model. Furthermore, the pH-responsive controlled release behavior at different pH (pH = 7.4, 6.5, and 5.0) was evaluated, and the results demonstrated that the cumulative release at pH 5.0 was 58.8 %, which was 2.7 times higher than that at pH 7.4, suggesting that the carrier exhibited a good pH sensitivity. The results of in vitro cellular experiments further indicated that CMCS-DFNS significantly improved the drug uptake efficiency in breast cancer MCF-7 cells. Importantly, the results of in vivo and cellular pharmacokinetic revealed that CMCS-DFNS can improve the circulation time and enhance the relative bioavailability of paclitaxel. Therefore, the fabricated pH-responsive drug delivery system has potential applications in the delivery of anti-tumor drugs, and provides a new delivery pathway for other compounds with low bioavailability.

One-Pot Preparation of HCPT@IRMOF-3 Nanoparticles for pH-Responsive Anticancer Drug Delivery

Metal–organic frameworks (MOFs) are considered to be promising materials for drug delivery. In this work, a Zinc-based MOF nanocomposite IRMOF-3 was introduced as a drug carrier for 10-hydroxycamptothecine (HCPT). Without an extra drug-loading process, a nanoscale drug delivery material HCPT@IRMOF-3 was prepared via one-pot synthesis. The composition and structure of the material were investigated, and the drug release character was measured. Compared with preparing IRMOF-3 first and loading the drug, the one-pot-prepared HCPT@IRMOF-3 exhibited a higher drug-loading capacity. The material presented pH-responsive release. The HCPT release rate at pH 5.0 was significantly higher than that at pH 7.4. The cytotoxicity experiments showed that IRMOF-3 was non-toxic, and HCPT@IRMOF-3 exhibited notable cytotoxicity to Hela and SH-SY5Y cells. One-pot synthesis is a simple and rapid method for the preparation of an MOF drug delivery system, and IRMOF-3 can be potentially used in pH-responsive drug delivery systems.

Development of amine-functionalized porous organosilica nanoparticles as pH-responsive drug delivery system

Development of amine-functionalized porous organosilica nanoparticles as pH-responsive drug delivery system

Enzymatically crosslinked magnetic starch-grafted poly(tannic acid) hydrogel for “smart” cancer treatment: An in vitro chemo/hyperthermia therapy study

A novel strategy was designed and developed based of horseradish peroxidase (HRP)-mediated crosslinking of tyramine-functionalized starch (Tyr-St), tannic acid (TA) and phenolated-magnetic nanoparticles (Fe3O4-PhOH NPs), and simultaneous loading of doxorubicin hydrochloride (Dox) to afford a pH-responsive magnetic hydrogel-based drug delivery system (DDS) for synergistic in vitro chemo/hyperthermia therapy of human breast cancer (MCF-7) cells. The developed St-g-PTA/Fe3O4 magnetic hydrogel showed porous micro-structure with saturation magnetization (δs) value of 19.2 emu g−1 for Fe3O4 NPs content of ∼7.4 wt%. The pore sizes of the St-g-PTA/Fe3O4 hydrogel was calculated to be 2400 ± 200 nm−2. In vitro drug release experiments exhibited the developed DDS has pH-dependent drug release behavior, while at physiological pH (7.4) released only 30 % of the loaded drug after 100 h. Human serum albumin (HSA) adsorption capacities of the synthesized St/Fe3O4 and St-g-PTA/Fe3O4 magnetic hydrogels were obtained as 86 ± 2.2 and 77 ± 1.9 μgmg−1, respectively. The well-known MTT-assay approved the cytocompatibility of the developed St-g-PTA/Fe3O4 hydrogel, while the Dox-loaded system exhibited higher anti-cancer activity than those of the free Dox as verified by MTT-assay, and optical as well as florescent microscopies imaging. The synergistic chemo/hyperthermia therapy effect was also verified for the developed St-g-PTA/Fe3O4-Dox via hot water approach.

PH-responsive resveratrol-loaded ZIF-8 nanoparticles modified with tannic acid for promoting colon cancer cell apoptosis.

Resveratrol (Res) is known for its potential in treating various types of cancers, with a particular advantage of causing minimal toxic side effects. However, its clinical application is constrained by challenges such as poor bioavailability, low water solubility, and chemical instability in neutral and alkaline environments. In light of these limitations, we have developed a pH-responsive drug delivery nanoplatform, Res@ZIF-8/TA NPs, which exhibits good biocompatibility and shows promise for in vitro cancer therapy. Benefiting from the mild reaction conditions provided by zeolitic imidazolate frameworks (ZIFs), a "one-pot method" was used for drug synthesis and loading, resulting in a satisfactory loading capacity. Notably, Res@ZIF-8/TA NPs respond to acidic environments, leading to an improved drug release profile with a controlled release effect. Our cell-based experiments indicated that tannic acid (TA) modification enhances the biocompatibility of ZIFs. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT assay), Hoechst 33342/PI staining, cell scratch assay, Transwell and Reverse Transcription quantitative PCR (RT-qPCR) assays further demonstrated that Res@ZIF-8/TA NPs inhibited colon cancer cell migration and invasion, and promoted apoptosis of colon cancer cells, suggesting a therapeutic potential and demonstrating anti-cancer properties. In conclusion, the Res@ZIF-8/TA NPs pH-responsive drug delivery systems we developed may offer a promising avenue for cancer therapy. By addressing some of the challenges associated with Res-based treatments, this system could contribute to advancements in cancer therapeutics.