pH-responsive Drug Delivery System Research Articles

Fabrication of a pH-responsive drug delivery system based on the super-paramagnetic metal-organic framework for targeted delivery of oxaliplatin

In this work, the magnetic metal-organic framework was synthesized based on a copper organic framework and Fe3O4 magnetic nanoparticles as a novel pH-responsive nanocarrier for oxaliplatin delivery. The magnetic metal-organic framework has been characterized by various analyses, such as Fourier transform infrared spectroscopy, thermogravimetric analysis, CHN analysis, and scanning electron microscopy. The application of the magnetic metal-organic framework as a pH-responsive nanocarrier for oxaliplatin is investigated through in vitro drug release experiments at simulated gastric (pH = 1.2) and simulated intestinal (pH = 7.4) fluids. About 35% of the oxaliplatin was released during 30 min in simulated gastric fluid, while 85% was released in simulated intestinal fluid in 9 h. The metal-organic framework indicated maximum adsorption capacity when the contact time at 10 min, the temperature of 25 °C, the initial concentration of the drug was 20 mg L−1, and pH = 7. Moreover, isotherm studies have shown that oxaliplatin adsorption via this magnetic metal-organic framework was of the Langmuir model.

Fabrication of a pH-Responsive Magnetic Nanocarrier Based on Carboxymethyl Cellulose-Aminated Graphene Oxide for Loading and In-Vitro Release of Curcumin

In this study, a pH-responsive magnetic drug delivery system was prepared by cross-linking of Cofe2O4/graphene oxide to carboxymethyl cellulose (CMC) biopolymer with adipic acid dihydrazide (ADH) and then investigated for loading and release of a poorly water-soluble anti-cancer drug, curcumin (CUR). The CoFe2O4/GO-ADH-CMC bio-nanocomposite was characterized by FE–SEM/EDX, TEM, FT–IR, XRD, TGA, VSM, and zeta-potential techniques. The highest amount of drug loading was achieved as 23.7 mg g–1 at 323 K, pH 6.0, and 120 mg L–1 CUR concentration. The study of adsorption isotherms revealed that the Sips model was best fitted to the equilibrium data (R2 > 0.997 and RMSE < 0.48), which indicated the contribution of both chemisorption and physisorption in drug loading. Furthermore, the release profile of CUR from drug-loaded CoFe2O4/GO-ADH-CMC was studied in mimicking the endosomal (pH = 5.6) and physiological (pH = 7.4) conditions. After 24 h, the maximum cumulative releases were found to be 86 and 38% at pH = 5.6 and 7.4, respectively. Also, the Peppas-Sahlin kinetic model was followed for the release data. The MTT assay exhibited good biocompatibility of the CoFe2O4/GO-ADH-CMC. The results implied that CoFe2O4/GO-ADH-CMC magnetic bio-nanocomposite might be utilized as a potentially safe carrier with the continuous and slow release of CUR.Graphical Abstract

Hydrazone modified nanoscale metal-organic frameworks as pH responsive nanoplatforms for cancer therapy

Practical clinical applications of chemotherapeutic drug are limited due to inevitable drawbacks such as low water solubility, big side effect and poor therapeutic efficiency. To overcome these drawbacks, we developed a novel nanoscale metal-organic framework (nMOFs)-based pH-responsive drug delivery system designed for efficient cancer therapy. In this work, a zirconium-based nMOFs UiO-66 was synthesized, and its surface was engineered to convert partial amino groups to hydrazone groups through stepwise organic transformations. Subsequently, the anticancer agent doxorubicin (DOX) served as a therapeutic drug and a fluorescent label was loaded through acid-labile hydrazone linkage to yield UiO-66-DOX. Acidic pH conditions (such as those surrounding tumor cells) catalyzed the hydrolysis of the hydrazone linkage and promoted the DOX release. These novel pH-sensitive drug delivery system will help to achieve safe delivery of the very cytotoxic chemotherapeutic drug (such as DOX), allowing to reduce the therapeutic dose and minimizing drug secondary effects.

Fabrication of pH responsive FU@Eu-MOF nanoscale metal organic frameworks for lung cancer therapy

Fabrication of biocompatible drug delivery systems (DDS) with enhanced permeation -retention effect and precise targeting is a major challenge in cancer therapy. The present study focused on fabrication of europium metal-organic framework (EuMOF) as pH responsive drug delivery system for sea weed polysaccharide fucoidan (FU@Eu-MOF) by one-pot synthesis method and assess its anticancer potential against lung cancer. Fabricated Eu-MOF exhibited high drug loading efficiency (22.15% by wt) and pH responsive controlled release of drug fucoidan (85.3 ± 0.02% in 48 h at pH 5.0). Material characterization revealed the formation of monodispersed uniform rod shaped structure decorated with fucoidan on the surface with average particle size of 71 ± 0.21 nm. Results of anticancer studies revealed that FU@Eu-MOF showed enhanced anticancer potential (IC50 value 32.17 ± 0.06 μg/ml) in lung cancer cells (A549) when compared to fucoidan alone (IC50 60.34 ± 0.03 μg/ml). Mechanism of anticancer potential revealed that FU@Eu-MOF enhanced ROS level inducing mitochondrial dysfunction and DNA damage leading to apoptosis. Safety evaluation studies revealed that FU@Eu-MOF showed neither cytotoxic, nor hemolytic activity under in vitro condition. To conclude the results of the study reveals FU@Eu-MOF as promising biocompatible material for drug delivery system for lung cancer therapy and other biomedical applications.

Guar gum-g-poly(N-acryloyl-L-phenyl alanine) based pH responsive smart hydrogels for in-vitro anticancer drug delivery

ABSTRACT In this study, modified natural polymeric-based pH-responsive hydrogels (GNAHs) were formulated using guar gum-grafted-poly(N-acryloyl phenyl alanine), 2-hydroxy ethyl acrylate, and 2-acrylamido-2-methyl-1-propane sulfonic acid. GNAH hydrogels were synthesized using a single-step radical polymerization reaction using N,N’-methylenebisacrylamide as a crosslinker and potassium persulfate as an initiator. The GNAH was used for the controlled release of Imatinib mesylate (IMS), an anticancer drug. The FTIR spectroscopy confirmed the IMS loading as well as grafting reaction between GG-g-PNPA and PHEA-co-PAMPS. This was further confirmed by XRD and DSC studies. The IMS also reduced the negative surface charge of the GNAH hydrogel. The microscopic images showed that the GNAH hydrogels have porous and canal structures with IMS molecules entrapped within the pores. The mode of drug release mechanism was assessed by applying various kinetic equations (non-Fickian diffusion mechanism, Higuchi square root and Korsmeyer–Peppas kinetic models) that showed pH-dependent drug release of hydrogels exhibiting an excellent controlled-release pattern for IMS for more than 48 h. Based on the drug release behavior of the as-synthesized amino acid-functionalized hydrogel, it can be suggested that GNAH hydrogels could also be used as a potential pH-responsive anticancer drug delivery system for other anticancer drugs.

Lipid-Coated CaCO3 Nanoparticles as a Versatile pH-Responsive Drug Delivery Platform to Enable Combined Chemotherapy of Breast Cancer.

The development of smart drug delivery nanocarriers for tumor-targeted delivery and controllable release of therapeutic agents is appealing to achieve effective cancer chemotherapy. We herein use CaCO3 nanoparticles as the core to load doxorubicin (DOX) and direct the assembly of amphiphilic oxaliplatin prodrugs (Pt(IV)) in the presence of other commercial lipids. The obtained DOX-Pt(IV)-CaCO3-PEG with excellent physiological stability exhibits instant pH-responsive degradation, thus enabling efficient pH-dependent release of DOX. Via detailed pharmacokinetic study, it is shown that DOX-Pt(IV)-CaCO3-PEG shows significantly improved pharmacokinetic behaviors compared to these free drugs, featured in prolonged blood circulation time and superior tumor homing efficacy. Resultantly, treatment with systemic administration of DOX-Pt(IV)-CaCO3-PEG was the most effective in suppressing the growth of tumors in Balb/c mice. This study highlights that our liposomal CaCO3 is a robust and biocompatible platform for preparing pH-responsive drug delivery systems, due to its multifaceted drug loading capacity, and thus is promising for potential clinical translation.

A Simple and Efficient Embolization-Combined Therapy for Solid Tumors by Smart Poly(amino acid)s Nanocomposites.

Interventional embolization and minimally invasive thermal ablation are common clinical methods for treatment of unresectable solid tumors, but they both have many insurmountable disadvantages. Inspired by pH-responsive drug delivery systems, we report the tumor microenvironment-gelled nanocomposites with poly[(l-glutamic acid-ran-l-tyrosine)-b-l-threonine-b-l-cysteine]s (PGTTCs) coating nanoparticles (NPs, Au or Fe3O4) for noninterventional targeted embolization combined with noninvasive thermal ablation therapy of solid tumors by intravenous injection without catheter use. The results of the animal trial in vivo with tumor-bearing mice and rabbits showed superior targeted embolization and therapy and fluorescence/single-photon emission computed tomography/magnetic resonance multimodal imaging effects. Tumors treated with NPs@PGTTCs were shrunken and necrotized within 30 days, the long-term survival rate was more than 80%, and the same effects can be achieved within 15 days when combined with thermal ablation. The method is so simple and efficient for many hard-to-treat tumors within an acidic microenvironment, which is not only a great improvement and innovation in tumor theranostics but also an important development in nanomedicine.

Laponite-Based Nanomaterials for Drug Delivery.

Laponite is a clay-based material composed of synthetic disk-shaped crystalline nanoparticles with highly ionic, large surface area. These characteristics enable the intercalation and dissolution of biomolecules in Laponite-based drug delivery systems. Furthermore, Laponite's innate physicochemical properties and architecture enable the development of tunable pH-responsive drug delivery systems. Laponite's coagulation capacity and cation exchangeability determine its exchange capabilities, drug encapsulation efficiency, and release profile. These parameters are exploited to design highly controlled and efficacious drug delivery platforms for sustained drug release. In this review, they provide an overview of how to design efficient delivery of therapeutics by leveraging the properties and specific interactions of various Laponite-polymer composites and drug moieties.

Smart pH-responsive drug release systems based on functionalized chitosan nanocomposite hydrogels

Chitosan (CS) was functionalized by formaldehyde (FA), acetaldehyde (AC), formaldehyde-urea (FA-U) and acetaldehyde-urea (AC-U) and the synthesized materials were utilized as efficient smart pH-responsive drug delivery systems (DDSs) for the cyclophosphamide (CP) anticancer drug. For this purpose, polymeric nanocomposite hydrogels were fabricated using CS-FA, CS-AC, CS-FA-U and CS-AC-U, carbon quantum dots (CQDs) as the filler as well as glycerol and the poly(ethylene oxide) (PEO) as plasticizers. The highest swelling degrees were happened in the acidic solution (2150–4300%), medium amounts in neutral pH (620–1250%) and the smallest values were observed within the alkaline pH (260–435%). The release percentages in three acidic, PBS buffer and alkaline solutions varied in the range of 64.5–77.7, 49.7–61.2 and 37.7–46.8%, respectively, illustrating a pH-responsive drug delivery which was approved by the statistical ANOVA tests. The CP release was significantly boosted within about 2–5 h, burst release, whereas release of the drug was subsequently slowly increased in 24 h demonstrating a sustained drug release. The kinetics of the drug release was examined for all of the DDSs and it was revealed that the Korsmeyer-Peppas was the best model as it was well matched to the drug release kinetics. The CS-FA-U-CQDs-CP and CS-AC-U-CQDs-CP were introduced as suitable slow-release drug carriers. It was finally found that the CS-AC-U-CP was the most desirable DDS as it simultaneously displayed favorable controlled, pH-responsive and high amount of drug release which followed the US Pharmacopeia drug release in acidic solution.

Theranostic mesoporous silica nanoparticles made of multi-nuclear gold or carbon quantum dots particles serving as pH responsive drug delivery system

Mesoporous silica nanoparticles are promising candidates to deliver proteins, antibodies, and anticancer drugs and to be served as an adsorbent of various types of substrate. Herein, a theranostic approach, in the preparation of fluorescence-type mesoporous silica for pH-responsive delivery of anticancer drug, doxorubicin, is introduced. By this mean, three types of mesoporous silica were synthesized. The ordinary type of mesoporous silica nanoparticles containing propylamine functional groups was synthesized by a controlled-size technique. Two types of fluorescence mesoporous silica were prepared, doped with gold or quantum dots nanoparticles. The fluorescence imaging has shown that the optical properties of the gold or carbon quantum dots have been transferred to the mesoporous matrix in doping processes. The as-prepared mesoporous materials were conjugated to doxorubicin via Schiff-base linkage. Several characterization techniques were utilized to detect the structure of the particles including FT-IR spectroscopy, XRD, N 2 adsorption/desorption, transition, and scanning electron microscopy. The amount of conjugated doxorubicin was analyzed by UV–Vis spectroscopy. The pH-responsive character was proved assessing the release profile in different pH ranges including physiological pH. The safety of the particles was evaluated by cell cytotoxicity assay on breast cancer cell line, MCF-7. As-prepared particles showed no cytotoxic behavior, but when they were loaded by doxorubicin, the appreciable release of the drug and subsequent cytotoxicity resulted against MCF-7 cells. The hemolytic study was conducted to prove the biocompatibility of these particles in the blood. Altogether, the proposed materials are suitable to be considered as safe and to be used as a theranostic platform for therapeutic and imaging purposes. • Three types of MSN were prepared and applied for drug delivery. • The fluorophore MSNs of GNP@MSN and QCD@MSN were organized for theranostic purpose. • DOX was conjugated to MSNs, and released through pH responsive profile. • The fluorophore MSNs showed biocompatibility and fluorescent contrast in MCF-7 cells. • MSNs@DOX showed toxicity in parallel and even higher than of free DOX in MCF-7 cell.

Application of Metal-Organic Frameworks as Ph-Responsive Drug Delivery System

Application of Metal-Organic Frameworks as Ph-Responsive Drug Delivery System

PH-Sensitive nanocarrier assisted delivery of adenosine to treat osteoporotic bone loss.

Bone tissue undergoes continuous remodeling via osteoclast-mediated bone resorption and osteoblast-mediated bone formation. An imbalance in this process with enhanced osteoclastic activity can lead to excessive bone resorption, resulting in bone thinning. Once activated, osteoclasts bind to the bone surface and acidify the local niche. This acidic environment could serve as a potential trigger for the delivery of therapeutic agents into the osteoporotic bone tissue. To this end, we developed a pH-responsive nanocarrier-based drug delivery system that binds to the bone tissue and delivers an osteoanabolic molecule, adenosine. Adenosine is incorporated into a hyaluronic acid (HA)-based nanocarrier through a pH-sensitive ketal group. The HA-nanocarrier is further functionalized with alendronate moieties to improve binding to the bone tissues. Systemic administration of the nanocarrier containing adenosine attenuated bone loss in ovariectomized mice and showed comparable bone qualities to that of healthy mice. Delivery of osteoanabolic small molecules that can contribute to bone formation and inhibit excessive osteoclast activity by leveraging the tissue-specific milieu could serve as viable therapeutics for osteoporosis.

A pH-responsive mesoporous silica nanoparticle-based drug delivery system for targeted breast cancer therapy.

In order to make the drug specifically aggregate at the tumor site, we had developed a targeted drug delivery system based on pH responsive mesoporous silica nanoparticles. Mesoporous silica nanoparticles (MSN-COOH) were prepared and doxorubicin (DOX) was loaded into the pores of MSN-COOH, and then polyethyleneimine (PEI) and anisamide (AA) were modified on the surface of mesoporous silica, named DOX@MSN-PEI-AA(DMPA). DMPA specifically entered tumor cells through AA-mediated receptor endocytosis; PEI dissociated from the surface of the MSN in the acidic environment of cellular lysosomes/endosomes due to protonation of PEI, resulting in steady release of the encapsulated DOX from the pores of MSN in the cytoplasm of the target cells. In vitro and in vivo anti-tumor experiments and hemolytic experiments indicated that DMPA can accurately target breast cancer cells and show excellent safety at the same time, showing great potential for tumor therapy.

The impact of MOFs in pH-dependent drug delivery systems: progress in the last decade.

Metal-organic frameworks (MOFs) are porous crystalline materials consisting of one-, two-, or three-dimensional networks created by metal ions/clusters and multidentate organic linkers through coordination bonding. MOFs are one of the most favorable candidates for biological applications such as wound dressings, cardiac prosthesis, tissue engineering, bioimaging, and drug delivery and as cancer theranostic systems due to their high surface area and porosity for the high loading of therapeutic agents and facile modification of their physical (e.g., pore size and shape) and chemical properties. Drug delivery involves the administration of drugs using a suitable carrier for achieving treatment without unwanted side effects. In the last few years, several types of MOFs have been synthesized including Zn-based MOFs, MIL series MOFs, and Zr-based MOFs and evaluated for their use in different biomedical fields, especially drug delivery. After Fe, zinc is the second most available element in the body, and hence Zn-based MOFs can be considered enduring platforms for various biomedical uses, especially drug delivery applications. MIL series composites and Zr-based biomaterials are also suggested for several biomedical applications due to their good mechanical properties, biocompatibility, and bioactivity. This review highlights the different types of Zn-based and MIL series MOFs that have been used as suitable pH-responsive drug delivery systems and summarizes the Zr-based MOFs that have been used as suitable pH-responsive or reverse pH-responsive drug delivery systems and also discuss their drug-releasing phenomenon at different pH ranges.

Charge reversal hairpin peptide modified synergy therapeutic nanoplatforms for tumor specific drug shuttling.

Given the distinct pathological features of neoplasm tissues, multifunctional responsive nanocarriers have been recently considered as promising candidates to optimize the chemotherapy regime. As a result, we propose a graphene oxide-based pH-responsive drug delivery system via covalent assembly of "hairpin-like" cell penetrating peptides with acid sensitive and charge reversal properties to realize superior tumor specificity and lower toxicity. Graphene oxide here can serve as high doxorubicin-loading nanosheets and facilitate swift drug release in response to laser irradiation, which provides an efficient platform for the synergy of photo-chemotherapy. Structurally, polyglycol conjugation on the graphene oxide surface fulfils the function of nanocomposite stabilization. After administration, the elaborately acid sensitive cell penetrating peptides maintain the hairpin structure under physiological conditions, while after entering the tumor acidic microenvironment, they undergo charge reversal and structural conversion to promote the cellular uptake of nanoparticles. The evaluation of nanocomposites in vitro revealed their negligible systematic toxicity and remarkable antitumor effects. In vivo experiments also confirmed the impressive stability and tumor-specific targeting for alleviating breast cancer. In conclusion, hairpin peptide modified graphene oxide nanoparticles show multiple merits including high drug carrying capacity, selective tumor penetration, responsive drug release and effective combination oncotherapy.

Supramolecular complexation with kinetic stabilization: cucurbit[6]uril encapsulated doxorubicin-based prodrugs for pH-responsive controlled release

Kinetically-stabilized host–guest complexation for the construction of a pH-responsive drug delivery system.

Advances in pH-responsive drug delivery systems

Bioresponsive nanosystems are increasingly important in a wide range of applications such as drug delivery, tissue engineering, imaging diagnostics and biosensors. Among these, pH-responsive delivery systems have gained considerable attention because of their ability in response to disease microenvironment and pH-triggered release of therapeutic drugs for therapy. In view of the importance of pH-sensitive nano-delivery systems, this review article highlights four types of pH-responsive modes, the corresponding design strategies, applications and future directions by smart design of pH-sensitive nanosystems for precision imaging or therapy.

Electrospun poly(NVCL-co-AA) fibers as potential thermo-and pH-sensitive agents for controlled release of hydrophobic drugs

In this study, poly(N-vinylcaprolactam-co-acrylic acid) (poly(NVCL-co-AA)) containing 20 and 30 mol% AA, were used to prepare thermo-and-pH-sensitive fibers containing a hydrophobic drug, ketoprofen, via electrospinning. Ketoprofen entrapment efficiency was assessed via UV–visible spectroscopy and revealed high values. The interaction drug/copolymer was investigated by FTIR, which indicated the drug entrapment into the fibers. The crystallinity of the ketoprofen-loaded fibers evaluated via DSC confirmed the presence of ketoprofen in its amorphous phase. Cytotoxicity of ketoprofen-loaded fibers was evaluated by cell viability assays using MTT. The results showed that the copolymer was not cytotoxic at a low ketoprofen concentration. The ketoprofen release profile was analyzed using independent and model-dependent approaches and showed slow-release rates at high temperatures. The study of the drug release mechanism showed that the Korsmeyer–Peppas model fits to the release behavior. These findings may expand poly(NVCL-co-AA) application making them promising candidates for temperature and pH responsive drug delivery systems.

PH-responsive supramolecular nanoparticles based on sulfobutylether7-β-CD/cationic surfactant and its controllable release of doxorubicin

Novel supramolecular nanoparticles were successfully built by sulfobutylether7-β-cyclodextrin and benzyl dodecyl dimethyl ammonium bromide. The assembly and disassembly behavior were determined by UV–Vis, Tyndall effect, dynamic light scattering, transmission electron microscopy, and zeta potential. Upon decreasing pH values, the resulting nanoparticles disassemble. The nanoparticles will be restored to spherical nanoparticles when the pH increases to the initial value. Due to the negative zeta potential, the nanoparticles showed good loading capacity for doxorubicin (DOX). DOX-loaded nanoparticles exhibited pH-responsive drug release behavior and possess higher cytotoxicity than the positive control, cisplatin. Thus, the simple and effective supramolecular nanoparticles with desirable load/release DOX property was constructed as pH-responsive drug delivery system.

PH low insertion peptide (pHLIP)-decorated polymeric nanovehicle for efficient and pH-responsive siRNA translocation

As a hallmark of most solid tumors, tumor acidic microenvironment aids tumor survival and progression. Tumor acidity also represents a tumor-specific stimulus that has been harnessed for the design and development of pH-responsive drug delivery systems. Pyruvate kinase M2 (PKM2) functions as an oncoprotein in tumorigenesis, and its overexpression in many tumors promotes metabolic rewiring towards aerobic glycolysis. Herein, a pH low insertion peptide (pHLIP)-functionalized copolymer of polyethylenimine and polylactide (pHLIP-PEI-PLA) was synthesized and self-assembled into a pH-responsive nanovehicle for delivery of siRNA to specifically target PKM2, a rate-limiting enzyme in glycolysis. The delivery of siPKM2 by pHLIP-decorated polymeric nanovehicle sufficiently downregulated the expression of PKM2 and exhibited potent inhibition on HepG2 cell migration. We believe that this strategy of targeting glycolysis-associated PKM2 gene by tumor acidity-responsive RNAi nanovehicle may offer a potential means for anticancer therapy.