pH-triggered Drug Delivery Research Articles

Hybrid crystalline bioparticles with nanochannels encapsulating acemannan from Aloe vera: Structure and interaction with lipid membranes

Smart nanocarrier-based bioactive delivery systems are a current focus in nanomedicine for allowing and boosting diverse disease treatments. In this context, the design of hybrid lipid-polymer particles can provide structure-sensitive features for tailored, triggered, and stimuli-responsive devices. In this work, we introduce hybrid cubosomes that have been surface-modified with a complex of chitosan-N-arginine and alginate, making them pH-responsive. We achieved high-efficiency encapsulation of acemannan, a bioactive polysaccharide from Aloe vera, within the nanochannels of the bioparticle crystalline structure and demonstrated its controlled release under pH conditions mimicking the gastric and intestinal environments. Furthermore, an acemannan-induced phase transition from Im3m cubic symmetry to inverse hexagonal HII phase enhances the bioactive delivery by compressing the lattice spacing of the cubosome water nanochannels, facilitating the expulsion of the encapsulated solution. We also explored the bioparticle interaction with membranes of varying curvatures, revealing thermodynamically driven affinity towards high-curvature lipid membranes and inducing morphological transformations in giant unilamellar vesicles. These findings underscore the potential of these structure-responsive, membrane-active smart bioparticles for applications such as pH-triggered drug delivery platforms for the gastrointestinal tract, and as modulators and promoters of cellular internalization.

Development and evaluation of a pH-responsive Mimosa pudica seed mucilage/β- cyclodextrin-co-poly(methacrylate) hydrogel for controlled drug delivery: In vitro and in vivo assessment

In this comprehensive investigation, a novel pH-responsive hydrogel system comprising mimosa seed mucilage (MSM), β-cyclodextrin (β-CD), and methacrylic acid (MAA) was developed via free radical polymerization technique to promote controlled drug delivery. The hydrogel synthesis involved strategic variations in polymer, monomer, and crosslinker content in fine-tuning its drug-release properties. The resultant hydrogel exhibited remarkable pH sensitivity, selectively liberating the model drug (Capecitabine = CAP) under basic conditions while significantly reducing release in an acidic environment. Morphological, thermal, and structural analyses proved that CAP has a porous texture, high stability, and an amorphous nature. In vitro drug release experiments showcased a sustained and controlled release profile. Optimum release (85.33 %) results were recorded over 24 h at pH 7.4 in the case of MMB9. Pharmacokinetic evaluation in healthy male rabbits confirmed bioavailability enhancement and sustained release capabilities. Furthermore, rigorous toxicity evaluations and histopathological analyses ensured the safety and biocompatibility of the hydrogel. This pH-triggered drug delivery system can be a promising carrier system for drugs involving frequent administrations.

Thermosensitive Hydrogel-Functionalized Mesoporous Silica Nanoparticles for Parenteral Application of Chemotherapeutics.

Hydrogels can offer many opportunities for drug delivery strategies. They can be used on their own, or their benefits can be further exploited in combination with other nanocarriers. Intelligent hydrogels that react to changes in the surrounding environment can be utilized as gatekeepers and provide sustained on-demand drug release. In this study, a hybrid nanosystem for temperature- and pH-sensitive delivery was prepared from MCM-41 nanoparticles grafted with a newly synthesized thermosensitive hydrogel (MCM-41/AA-g-PnVCL). The initial particles were chemically modified by the attachment of carboxyl groups. Later, they were grafted with agar (AA) and vinylcaprolactam (VCL) by free radical polymerization. Doxorubicin was applied as a model hydrophilic chemotherapeutic drug. The successful formulation was confirmed by FT-IR and TGA. Transmission electron microscopy and dynamic light scattering analysis showed small particles with negative zeta potential. Their release behaviour was investigated in vitro in media with different pH and at different temperatures. Under tumour simulating conditions (40 °C and pH 4.0), doxorubicin was almost completely released within 72 h. The biocompatibility of the proposed nanoparticles was demonstrated by in vitro haemolysis assay. These results suggest the possible parenteral application of the newly prepared hydrogel-functionalized mesoporous silica nanoparticles for temperature-sensitive and pH-triggered drug delivery at the tumour site.

PH-Responsive Hybrid Nanoassemblies for Cancer Treatment: Formulation Development, Optimization, and In Vitro Therapeutic Performance.

Current needs for increased drug delivery carrier efficacy and specificity in cancer necessitate the adoption of intelligent materials that respond to environmental stimuli. Therefore, we developed and optimized pH-triggered drug delivery nanoassemblies that exhibit an increased release of doxorubicin (DOX) in acidic conditions typical of cancer tissues and endosomal vesicles (pH 5.5) while exhibiting significantly lower release under normal physiological conditions (pH 7.5), indicating the potential to reduce cytotoxicity in healthy cells. The hybrid (polymeric/lipid) composition of the lyotropic non-lamellar liquid crystalline (LNLCs) nanoassemblies demonstrated high encapsulation efficiency of the drug (>90%) and high drug loading content (>7%) with colloidal stability lasting at least 4 weeks. Confocal microscopy revealed cancer cellular uptake and DOX-loaded LNLCs accumulation near the nucleus of human hepatocellular carcinoma cells, with a large number of cells appearing to be in apoptosis. DOX-loaded LNLCs have also shown higher citotoxicity in cancer cell lines (MDA-MB 231 and HepG2 cell lines after 24 h and in NCI-H1299 cell line after 48 h) when compared to free drug. After 24 h, free DOX was found to have higher cytotoxicity than DOX-loaded LNLCs and empty LNLCs in the normal cell line. Overall, the results demonstrate that DOX-loaded LNLCs have the potential to be explored in cancer therapy.

PH-Responsive Metal-Organic Framework Thin Film for Drug Delivery.

In this work, surface-supportive MIL-88B(Fe) was explored as a pH-stimuli thin film to release ibuprofen as a model drug. We used surface plasmon resonance microscopy to study the pH-responsive behaviors of MIL-88B(Fe) film in real time. A dissociation constant of (6.10 ± 0.86) × 10-3 s-1 was measured for the MIL-88B(Fe) film in an acidic condition (pH 6.3), which is about 10 times higher than the dissociation of the same film in a neutral pH condition. MIL-88B(Fe) films are also capable of loading around 6.0 μg/cm2 of ibuprofen, which was measured using a quartz crystal microbalance (QCM). Drug release profiles were compared in both acidic and neutral pH conditions (pH 6.3 and 7.4) using a QCM cell to model the drug release in healthy body systems and those containing inflammatory tissues or cancerous tumors. It was found that the amount of drug released in acidic environments had been significantly higher compared to that in a neutral system within 55 h of testing time. The pH-sensitive chemical bond breaking between Fe3+ and the carboxylate ligands is the leading cause of drug release in acidic conditions. This work exhibits the potential of using MOF thin films as pH-triggered drug delivery systems.

Dual-Drug Conjugated Glyco-Nanoassemblies for Tumor-Triggered Targeting and Synergistic Cancer Therapy.

Drug-conjugated nanoassemblies potentiate the efficiency of anticancer drugs through the advantages of high drug-loading capacity and passive/active targeting ability in cancer therapy. This study describes the synthesis of gemcitabine (Gem) and cisplatin (cisPt) dual-drug-functionalized glyco-nanoassemblies (GNs) for anticancer drug delivery systems. It also investigates the pH-triggered drug delivery of the conventional anticancer drug cisPt. A Gem-functionalized well-defined glycoblock copolymer backbone (P(iprFruMA-b-MAc)-Gem), which consists of fructose and methacrylic acid segments, was synthesized via a reversible addition-fragmentation chain transfer (RAFT) polymerization method. Following the hydrolysis of the protecting groups on the backbone copolymer, cisPt functionalization of P(FruMA-b-MAc)-Gem in aqueous media was carried out during the transformation of glycoblock polymers into self-assembled spherical glyco-nanoassemblies (GN3). Monodrug-functionalized glyco-nanoassemblies were also prepared either with Gem (GN1) or cisPt (GN2) to compare the synergetic effect of dual-drug conjugated glyco-nanoassemblies (GN3). The sizes of glyco-nanoassemblies GN1, GN2, and GN3 were found as 5.76 ± 0.64, 59.80 ± 0.13, and 53.80 ± 3.90 nm and dispersity (Đ) values as 0.476, 0.292, and 0.311 by dynamic light scattering (DLS) measurement, respectively. The in vitro studies revealed that the drug-free glyco-nanoassemblies are biocompatible at concentrations higher than 296 μg/mL. The drug-conjugated glyco-nanoassemblies (GN1 and GN2) exhibited in vitro cytotoxicity against human breast cancer cell lines of MDA-MB-231 comparable to free Gem and cisPt, illustrating an efficient drug release into the tumor environment. Additionally, GNs exhibited higher selectivity and preferential cellular internalization in MDA-MB-231 when compared to healthy cell lines of CCD-1079Sk. These dual-drug conjugated GNs can effectively enhance the killing of cancer cells and increase synergistic chemotherapy.

Sonochemical route for mesoporous silica-coated magnetic nanoparticles towards pH-triggered drug delivery system

This work reports a pH-triggered release system based on core@shell mesoporous magnetic nanoparticles (MNP@mSiO 2 ) obtained using a simple and rapid ultrasound-assisted method. Performed characterization reveals magnetic cores of Fe 2.9 Mn 0.1 O 4 (38 ± 6 nm) and specific loss power values adequate for hyperthermia (463 W/g), surrounded by a mesoporous silica shell (10 ± 2 nm) with large surface area (269 m 2 g -1 ) functionalized with hydroxyl groups (-OH). MNP@mSiO 2 were loaded with DOX and amino-silane grops, providing pH-triggered DOX release at acidic environments, driving by dipolar intermolecular interactions. The experimental DOX release kinetics at pH 5.5, 6.6 and 7.4 were determined and adjusted to Gompertz dissolution model (Nash–Sutcliffe efficiency coefficient (NSE>0.9)), where the only strongly pH-dependent variable is the percentage of DOX released. The pH-triggered response observed in the system was ~20% of the DOX loaded into the MNP@mSiO 2 is released at pH 6.6 or 7.4, whereas up to 80 wt% is released at pH 5.5. Time to 50% of release and dissociation rate of the system remaining constant, suggesting no-pH influence on these parameters. The biological assays highlight negligible hemolytic effect and cytocompatibility of the hybrid material, pointing out the potential use of MNP@mSiO 2 as a magnetic driven drug delivery system with pH-triggered drug release kinetics at acidic environments. These results probe the feasibility of sonochemical methods in the elaboration of biocompatible and controlled properties nanomaterials for drug release applications, with the advantage of accurately responses predictions by mathematical model and using minimal processing steps or laboratory equipment.

PH-Sensitive Drug Delivery System Based on Mesoporous Silica Modified with Poly-L-Lysine (PLL) as a Gatekeeper.

In this work, we synthesized a novel pH-triggered drug delivery system to enhance the bioavailability of the anticancer drug doxorubicin (DOX) through the gatekeeper poly-L-lysine (PLL) on the pore entrances of mesoporous silica nanoparticles (MSNs). Firstly, mesoporous silica was selected as the inorganic support for drug loading. Secondly, PLL was employed as the gatekeeper to control the cargo transport. In a neutral environment, the PLL brushes became shrunken and formed a dense barrier on the pore entrances of PLL/MSNs, which closed the pores and thus prevented the release of cargo. In an acidic environment, the cargo was released from the carrier PLL/MSNs because the pore entrances were opened by the swollen PLL brushes. The DOX-loaded PLL/MSNs (PLL/MSNs-DOX) showed 1.5 times higher drug release under acidic condition (pH = 4) than under neutral condition (pH = 7). During the drug release experiment for 48 h under acidic condition, PLL/MSN-DOX released about 50% of the drug after 9 h and approximately 85% after 24 h, whereas pristine MSNs loaded with DOX (MSNs-DOX) released about 50% of the drug after 30 min and reached equilibrium after 24 h. The MSNs also demonstrated their effectiveness in storing anticancer drugs until the desired environmental trigger is present. Therefore, the pH-responsive MSNs have great potential as a targeting cancer therapy.

Expedition of Eudragit® Polymers in the Development of Novel Drug Delivery Systems.

Eudragit® polymer has been widely used in film-coating for enhancing the quality of products over other materials (e.g., shellac or sugar). Eudragit® polymers are obtained synthetically from the esters of acrylic and methacrylic acid. For the last few years, they have shown immense potential in the formulations of conventional, pH-triggered, and novel drug delivery systems for incorporating a vast range of therapeutics including proteins, vitamins, hormones, vaccines, and genes. Different grades of Eudragit® have been used for designing and delivery of therapeutics at a specific site via the oral route, for instance, in stomach-specific delivery, intestinal delivery, colon-specific delivery, mucosal delivery. Further, these polymers have also shown their great aptitude in topical and ophthalmic delivery. Moreover, available literature evidences the promises of distinct Eudragit® polymers for efficient targeting of incorporated drugs to the site of interest. This review summarizes some potential researches that are being conducted by eminent scientists utilizing the distinct grades of Eudragit® polymers for efficient delivery of therapeutics at various sites of interest.

Graphene quantum dot cross-linked carboxymethyl cellulose nanocomposite hydrogel for pH-sensitive oral anticancer drug delivery with potential bioimaging properties

Herein, graphene quantum dots (GQDs) were introduced as a novel and safe crosslinker for carboxymethyl cellulose to make biodegradable and biocompatible hydrogels. The casting was used as a simple method for the preparation of the CMC/GQDs films. Effects of the GQDs percentage on the physicochemical properties of the films were studied, and several characterizations were performed including Fourier transform infrared spectroscopy, UV–vis spectroscopy, scanning electron microscopy, gas permeability, and mechanical testing analysis. The CMC/GQDs showed a pH-sensitive swelling and degradation with improved tensile strength. Fluorescent properties were also studied to evaluate the potential of the prepared CMC/GQDs nanocomposite for fluorescent bioimaging applications. Drug delivery property of the CMC-GQDs were studied using doxorubicin (DOX) as a model anticancer drug. Cytotoxicity studies were carried out using human colon adenocarcinoma HT29 cells. The prepared CMC/GQDs exhibited biocompatibility and pH-sensitive drug delivery behavior which proposed the prepared nanocomposite hydrogel has the potential to be used as a pH-triggered site-specific drug delivery system.

Integrated prodrug micelles with two-photon bioimaging and pH-triggered drug delivery for cancer theranostics.

Nanodrug carriers with fluorescence radiation are widely used in cancer diagnosis and therapy due to their real-time imaging, less side effect, better drug utilization as well as the good bioimaging ability. However, traditional nanocarriers still suffer from unexpectable drug leakage, unsatisfactory tumor-targeted drug delivery and shallow imaging depth, which limit their further application in cancer theranostics. In this study, an integrated nanoplatform is constructed by polymeric prodrug micelles with two-photon and aggregation-induced emission bioimaging, charge reversal and drug delivery triggered by acidic pH. The prodrug micelles can be self-assembled by the TP-PEI (DA/DOX)-PEG prodrug polymer, which consists of the two-photon fluorophore (TP), dimethylmaleic anhydride (DA) grafted polyethyleneimine (PEI) and polyethylene glycol (PEG). The PEG segment, DOX and DA are bridged to polymer by acid cleavable bonds, which provides the micelles a ‘stealth’ property and a satisfactory stability during blood circulation, while the outside PEG segment is abandoned along with the DA protection in the tumor acidic microenvironment, thus leading to charge reversal-mediated accelerated endocytosis and tumor-targeted drug delivery. The great antitumor efficacy and reduced side effect of these pH-sensitive prodrug micelles are confirmed by antitumor assays in vitro and in vivo. Meanwhile, these micelles exhibited great deep-tissue two-photon bioimaging ability up to 150 μm in depth. The great antitumor efficacy, reduced side effect and deep two-photon tissue imaging make the TP-PEI (DA/DOX)-PEG prodrug micelles would be an efficient strategy for theranostic nanoplatform in cancer treatment.

Disulfide-cleavage- and pH-triggered drug delivery based on a vesicle structured amphiphilic self-assembly.

Hydrophilic poly (acrylic acid) (PAA) and hydrophobic α-tocopherol succinate (TOS) were integrated via a two-step amidation with cystamine (Cys) as the linkage, and then the self-assembly of amphiphilic PAA-cys-TOS occurred in the aqueous solution of methotrexate (MTX), an anti-cancer drug, resulting a vesicle structured drug carrier. Since the disulfide (-S-S-) bridge of Cys is sensitive to glutathione (GSH) and the amide bonds in PAA-cys-TOS are sensitive to pH, disulfide-cleavage- and pH-triggered drug delivery was achieved with the amphiphilic self-assembly. Of particular interest was that the topography of the self-assembly varied remarkably during the triggered delivery, which was indicated by TEM results.

Core-shell-corona chitosan-based micelles for tumor intracellular pH-triggered drug delivery: Improving performance by grafting polycation

Core-shell-corona chitosan-based micelles were designed for the tumor intracellular pH-triggered doxorubicin (DOX) delivery, via a facile in-situ micellization in an aqueous solution of DOX and polyethylene glycol (PEG) and poly(2-(diisopropylamino) ethyl methacrylate) (PDPA) dual-modified chitosan (PEG-g-CS-g-PDPA). The effect of the PDPA modification on the diameter, drug loading-capacity (DLC) and pH-triggered drug release was investigated for the three different polymerization degrees of PDPA (25, 32, and 42) with a similar modification degree of ~22%. The optimized ones, the core-shell-corona DOX/PEG-g-CS-g-PDPA32 micelles possessed a mean hydrodynamic diameter (Dh) of 211 nm and DLC of 54%, showing an excellent pH-triggered drug release with negligible premature drug leakage in 60 h. Such results indicated that grafting polycation could efficiently improve the performance of the chitosan-based drug delivery system (DDS) for tumor chemotherapy.

ZnO-functionalized mesoporous inner-empty nanotheranostic platform: upconversion imaging guided chemotherapy with pH-triggered drug delivery

Here we report a novel drug delivery system using mesoporous inner-empty upconversion microspheres carrying drugs with ZnO quantum dots (UCMPS@ZnO) acting as a ‘door-keeper’ for pH-triggered drug release. Compared to other upconversion drug delivery systems, it is smarter, simpler, more efficient and more biocompatible. In particular, the UCMPS@ZnO microspheres show low cytotoxicity, are simple to produce and have a high drug loading rate (15%). Promisingly, a mice treatment experiment demonstrated that the multifunctional nanoparticles have efficient inhibition of tumor growth after a 14-day treatment. This makes UCMPS@DOX–ZnO microspheres a promising theranostic candidate in cancer treatment and clinical trials.

“pH-triggered” drug release using shell cross-linked micelles from aqueous RAFT-synthesized PAPMA-b-PNIPAM copolymers

A new polymer namely poly (N-(3-aminopropyl) methacrylamide)-b-poly(N-isopropylacrylamide) (PAPMA-b-PNIPAM) was made for pH-triggered drug delivery by means of aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. PAPMA-b-PNIPAM was hydrophilic at 25 °C, and micelles were formed at 39 °C. The PAPMA chain was crosslinked with terephthaldicarboxaldehyde at pH = 9.0 and shell cross-linking (SCL) micelles were prepared. The sizes of the SCL micelles were 45~65 nm which can be reversible dissociated under acidic conditions. The formation of temperature-responsive SCL micelles and their cleavage behaviours were characterized.

AIEgens-functionalised hydroxyapatite rods for explosive detection in water and pH-triggered drug delivery

Aggregation-induced emission luminogens (AIEgens) and carboxylic groups functionalised hydroxyapatite rods were prepared by a one-pot condensation process. The obtained materials emit strong blue light centered at 479nm under UV irradiation, exhibiting typical AIE property. Such materials can serve as efficient fluorescent sensors for the detection of explosive picric acid (PA), with excellent quenching constant of 3.3×104M−1 in the water solution. In addition, the obtained materials can react with the drug molecules such as anticancer drug doxorubicin (DOX) through hydrazone bond, and serve as effective pH-triggered drug release systems, showing potential application in biomedicine.

Development of itaconic acid-based molecular imprinted polymers using supercritical fluid technology for pH-triggered drug delivery

A novel pH-responsive molecularly imprinted polymer (MIP) based on Itaconic acid:Ethylene glycol dimethacrylate was developed as a potential body-friendly oral drug delivery system for metronidazole (MZ), a pH-independent drug. MIP performance was evaluated in a simulated oral administration situation, at pHs 2.2 and 7.4. Itaconic acid-based copolymers were synthesized using two different molar ratios of template:monomer:crosslinker (T:M:C), 1:5:25 and 1:5:50, in supercritical carbon dioxide (scCO2) in high yields. Further, impregnation of MZ was performed in scCO2 environment. Morphological and chemical properties of the copolymers produced were assessed by SEM, Morphologi G3 and FTIR analyses. Non-molecularly imprinted polymer (NIP) matrices presented swelling over time in opposition to the molecularly imprinted ones. In the scCO2-impregnation process, MIPs showed a significant molecular recognition towards MZ, presenting higher drug uptake ability with MZ loading of 18-61 wt% in MIPs, compared to 7–20 wt% in NIPs. In vitro drug release experiments presented different release profiles at the different pHs, where MZ-MIPs could release higher amounts of MZ at the lowest pH than at pH 7.4.

Preparation of a mesoporous silica-based nano-vehicle for dual DOX/CPT pH-triggered delivery

A dual doxorubicin/camptothecin (DOX/CPT) pH-triggered drug delivery mesoporous silica nanoparticle (MSN)-based nano-vehicle has been prepared. In this drug-delivery system (DDS), CPT is loaded inside the pores of the MSNs, while DOX is covalently attached to the surface of an aldehyde-functionalized MSN through a dihydrazide–polyethylene glycol chain. Thus, DOX and the linker act as pH-sensitive gatekeeper. The system is versatile and easy to assemble, not requiring the chemical modification of the drugs. While at physiological conditions the release of the drugs is negligible, at acidic pH a burst release of DOX and a gradual release of CPT take place. In vitro cytotoxicity tests have demonstrated that this DDS can deliver efficiently DOX and CPT for combination therapy.

Gold Nanorods Stabilized by Biocompatible and Multifunctional Zwitterionic Copolymer for Synergistic Cancer Therapy.

A zwitterionic copolymer between methacryloyloxyethyl phosphorylcholine (MPC) and methacrylic acid (MA), PMAMPC is introduced as a potential versatile polymeric stabilizer for gold nanorods (AuNRs). The MA units in the copolymer serve as built-in feature for multiple functionalization, namely introducing additional thiol groups as active sites for binding with the AuNRs and conjugating with doxorubicin (DOX), an anticancer drug via acid-labile hydrazone linkage. The MPC units, on the other hand, provide biocompatibility and antifouling characteristics. The chemically modified PMAMPC can act as an effective stabilizer for AuNRs yielding PMAMPC-DOX-AuNRs with a fairly uniform size and shape with good colloidal stability. In vitro cytotoxicity suggested that PMAMPC can not only improve the AuNRs biocompatibility, but also decrease DOX toxicity to a certain extent. The PMAMPC-DOX-AuNRs were efficiently internalized inside cancer cells and localized in lysosomes, where DOX was presumably acid-triggered released as monitored by confocal laser scanning microscopic analysis and flow cytometry. Furthermore, the combined photothermal-chemo treatment of cancer cells using PMAMPC-DOX-AuNRs exhibited a higher therapeutic efficacy than either single treatment alone. These results suggested that the PMAMPC-DOX-AuNRs could potentially be applied in pH-triggered drug delivery for synergistic cancer therapy.

Core-Shell-Corona Silica Hybrid Nanoparticles Templated by Spherical Polyelectrolyte Brushes: A Study by Small Angle X-ray Scattering.

Core-shell-corona silica/polymer hybrid nanoparticles with narrow size distribution were prepared in the template of spherical polyelectrolyte brushes (SPB) which consist of a solid polystyrene (PS) core densely grafted with linear poly(acrylic acid) (PAA) chains. The microstructure of obtained hybrid nanoparticles was studied by small-angle X-ray scattering (SAXS) and in combination with dynamic light scattering (DLS) and transmission electron microscopy (TEM). The generation of silica shell within the brush is confirmed by the significant increase of the electron density in the shell, and the silica shell showed a unique inner-loose-outer-dense structure, whose thickness is pH sensitive but is insensitive to ionic strength as revealed by fitting SAXS data. After dissolving the PS core, hollow silica nanoparticles were obtained and determined by SAXS, which should be ideal carriers for pH-triggered drug delivery. SAXS is confirmed to be a powerful method to characterize the core-shell-corona silica/polymer hybrid and hollow silica nanoparticles.