pH-responsive Drug Carriers Research Articles

Self-assembled tannic acid complexes for pH-responsive delivery of antibiotics: Role of drug-carrier interactions

Self-assembled particles, based on non-covalent interactions, are attractive drug carriers with a relatively simple structure and easy preparation. Tannic acid (TA) is an anionic polyphenolic compound with a wide range of molecular interactions and diverse applications in drug delivery research. Here, we propose the use of TA complexes with cationic antibiotics as a new pH-responsive drug carrier of high drug loading and optimal stability. TA complexes were prepared with three water-soluble antibiotics; colistin sulfate (COL), gentamicin sulfate (GEN) and gatifloxacin (GAT). Complexes’ size ranged from several-hundred nanometers to few microns. For selected particles, drug loading ranged from 30 to 36%. Importantly, we demonstrate the impact of drug-carrier interactions, studied via infrared spectroscopy and molecular modeling, on final complex stability and performance; the complexes resisted dissociation in presence of serum at physiological pH to variable degrees and showed different drug release profiles. However, all complexes dissociated upon medium acidification, releasing their drug payload and demonstrating expected antibacterial effect. These results demonstrate that TA/antibiotic self-assembled complexes represent an excellent carrier for pH-sensitive delivery of water-soluble drugs. In addition to system’s simplicity and low cost, complexes were easily prepared with high drug loading and desirable pH-dependent association/dissociation profile.

Luminescent Lanthanide-Collagen Peptide Framework for pH-Controlled Drug Delivery.

Collagen mimetic scaffolds play a pivotal role in regenerative medicine and tissue engineering due to their extraordinary structural and biological features. We have herein, for the first time, reported the construction of luminescent lanthanide-collagen peptide hybrid three-dimensional nanofibrous scaffolds, which well mimic the characteristic architectural structure of native collagen. Three collagen mimetic peptides, composed of repetitive central (GPO)7 sequences and altered terminal amino acids, have been shown to consistently self-assemble to form biocompatible nanofibers under the trigger of a variety of lanthanide ions, which also functionalize the assembled materials with easily tunable photoluminescence. Furthermore, the collagen peptide-lanthanide hybrid scaffolds possess programmable pH-responsive features. The lanthanide ion-mediated assembly of all three collagen peptides are conveniently and reversibly regulated by pH, while their pH-dependent patterns are finely tuned by the identity of terminal amino acids. Using camptothecin and cefoperazone sodium as two model drugs, the drug-loading and releasing efficiency of the collagen peptide-lanthanide scaffolds are nicely modulated by pH, demonstrating the efficacy of these nanofibrous scaffolds as pH-responsive drug carriers. These novel luminescent collagen peptide-lanthanide scaffolds provide a facile system for pH-controlled drug delivery, suggesting promising applications in the development of therapies for many diseases.

Linear and Hyperbranched Copolymers of PEG-Based Acrylates and Methacrylic Acid as pH-Responsive Hydrophobic Drug Carriers

The oral administration of pharmaceuticals is typically preferred over other methods due to its non-intrusiveness and convenience of administration. However, the varying chemical environments of the gastro-intestinal tract pose a challenge in ensuring the stability and inertness of a drug compound until it reaches its target. Polymers that are responsive to pH changes have potential as smart materials for the controlled oral administration of pharmaceuticals. In this study, linear and hyperbranched copolymers of methacrylic acid (MAA) and poly (ethylene glycol) methyl ether methacrylate (PEGMEMA) were synthesized by RAFT polymerization. High molecular weight polymers were produced with PDI values close to 1.0. These smart materials underwent phase changes at pH 5.15-5.6. This property enabled the amphiphilicity of the copolymers to be switched on or off. By doing so inin vitrodrug release studies with ibuprofen as the model hydrophobic drug, the copolymers were able to inhibit drug release in simulated stomach conditions to up to 13% while enhancing drug release in simulated intestinal conditions to up to 75% within 6 hours. These indicate that copolymers based on MAA and PEGMEMA have potential as smart materials for drug delivery applications.

Derivative of Epigallocatechin-3-gallatea Encapsulated in ZIF-8 with Polyethylene Glycol-Folic Acid Modification for Target and pH-Responsive Drug Release in Anticancer Research.

Epigallocatechin-3-gallatea (EGCG), a key component of tea, has been found to have anticancer activity but poor stability. To improve its antioxidative stability and widen the application of EGCG in anticancer therapy, a kind of EGCG derivative, EGCG palmitate (PEGCG), was synthesized and encapsulated in ZIF-8 nanoparticles with functionalization of folic acid (FA), which is commonly used as pH-responsive drug carrier. PEGCG encapsulated in polyethylene glycol (PEG)-FA/ZIF-8 nanoparticles (PEG-FA/PEGCG@ZIF-8 NPs) exhibits sixfold improvement of stability compared to that of free PEGCG. With target recognition between folic acid (FA) on the surface of NPs and overexpressed FA receptor (FR) in cancer cells, the NPs can be efficiently internalized into cells and present targeted effects of inhibition growth on HeLa cells (cancer cells) compared with HEK 293 cells (normal cells), consistent with the regulation of reactive oxygen species (ROS) level and the induction of autophagy. The detection of autophagy flux and the measurement of autophagy marked proteins in cells suggest that autophagy flux and the autophagosome formation are appreciably induced when the cells were treated with PEG-FA/PEGCG@ZIF-8 NPs. It indicates that pH-responsive PEG-FA/PEGCG@ZIF-8 NPs with target identification for cancer cells can be used as highly efficient drug carriers in targeting cancer chemotherapy.

Molecular Insights into the Effects of Media-Drug and Carrier-Drug Interactions on pH-Responsive Drug Carriers.

We have performed two sets of all atom molecular dynamics (MD) simulations of poly(acrylic acid) (PAA) oligomers, considered as a model pH-responsive drug carrier. In the first set, multiple oligomers of PAA are simulated in model gastric and intestinal fluids, where the degree of deprotonation of PAA oligomers is varied with the medium pH. Since the gastric fluid has a pH substantially lower than that of intestinal fluid, PAA is relatively lesser ionized in gastric fluid and forms aggregates. In the second set, we simulated multiple oligomers of PAA with multiple molecules of a cationic anticancer drug, doxorubicin (DOX), for a range of pH values representative of various physiological conditions. The diffusion coefficient of DOX decreases with an increase in pH due to an increase in the ionic complexation of PAA with DOX, despite a decrease in PAA aggregation. Our findings are in agreement with recent experimental reports on pH-triggered targeting of tumor cells by the PAA-DOX system. Results of these two sets of studies establish that both carrier aggregation and carrier-drug interactions are competing influences that together determine the drug release from pH-responsive polymers.

Aspartic acid functionalized PEGylated MSN@GO hybrid as an effective and sustainable nano-system for in-vitro drug delivery

PurposeIn this research, aspartic acid functionalized PEGylated mesoporous silica nanoparticlesgraphene oxide nanohybrid (As-PEGylated-MSN@GO) prepared as a pH-responsive drug carrier for the curcumin delivery. For better camouflage during blood circulation, poly(ethylene glycol) was decorated on the surface of MSN@GO nanohybrid. Materials and methodsThe nanocarrier was characterized by using X-ray powder diffraction (XRD), dynamic light scattering (DLS), UV–vis spectroscopy, thermal gravimetry analysis (TGA), FT-IR, SEM and TEM. ResultsThe size of modified MSN@GO was around 75.8 nm and 24% wt. of curcumin was loaded on the final nanohybrid. pHdecrement from 7.4 to 5.8 the release medium led to increase the cumulative amount of drug release from 54% to 98%. ConclusionsAs-functionalized MSN@GO had no cytotoxicity against human breast adenocarcinoma (MCF-7) and human mammary epithelial (MCF10A) as cancerous and normal cell lines, respectively. Whereas curcuminloaded nanohybrid showed excellent killing capability against MCF-7 cells.

PH-responsive mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin against osteosarcoma

Oral or intravenous chemotherapy is an important strategy to treat metastatic cancer, but it may cause systemic toxicity for healthy tissue. Herein, we for the first time fabricated mesoporous ZSM-5 zeolites/chitosan core-shell nanodisks loaded with doxorubicin (ZSM-5/CS/DOX) as drug delivery systems against osteosarcoma. The mesoporous ZSM-5 zeolites exhibited disk-like shapes with thicknesses of 100nm and diameters of 300nm, and the mesopores with pore sizes of 3.75nm were originated from desilication treatment. The pH-responsive ZSM-5/CS/DOX nanodisks possessed a great drug loading efficiency of 97.7%, and their controlled release trends of DOX were fitted well with the Korsmeyer-Peppas model. The DOX could be efficiently released the ZSM-5/CS/DOX nanodisks after cellular endocytosis and induced cancer cells apoptosis. Moreover, the pH-responsive drug carriers led to efficient tumor inhibition with low side effects, especially cardiac toxicity, as confirmed by pharmacokinetic study, serological examination and H&E staining assays. Therefore, the ZSM-5/CS/DOX nanodisks are a promising pH-responsive drug carrier for targeted cancer therapy.

A novel intracellular pH-responsive formulation for FTY720 based on PEGylated graphene oxide nano-sheets

Objective: This study was performed to investigate a novel pH-responsive nanocarrier based on modified nano graphene oxide (nGO) to promote the acid-triggered intracellular release of a poorly soluble drug, FTY720.Methods: To synthesize a drug conjugated to modified nGO, first the polyethylene glycol (PEG) was conjugated to nGO, then the produced PEG-nGO was functionalized with the anticancer drug, FTY720, through amide bonding. It was characterized by the scanning electron microscopy (SEM), the atomic force microscopy (AFM), the Fourier transform infrared (FTIR) spectroscopy and the UV–vis spectroscopy. In vitro drug release of the FTY720-conjugated PEG-nGO was evaluated at pH 7.4 and 4.6 PBS at 37 °C. Furthermore, the antineoplastic action of unloaded and drug-loaded carrier against the human breast adenocarcinoma cell line MCF7 was explored using MTT and BrdU assays.Results: Characterization methods indicated successful drug deposition on the surface of nGO. In vitro, drug release results revealed a significantly faster release of FTY720 from PEG-nGO at acidic pH, compared with physiological pH. The proliferation assays proved that the unloaded nGO had no significant cytotoxicity against MCF7 cells, while free FTY720- and FTY720-loaded PEG-nGO had an approximately equal cytotoxic effect on the MCF7 cells. It was found that the extended release characteristic of FTY720 was well fitted to Korsmeyer–Peppas model and the release profile of FTY720 from PEG-nGO is diffusion controlled.Conclusion: PEGylated GO can act as a pH-responsive drug carrier to improve the efficacy of anticancer drug delivery.

Ultrasonically assisted preparation of poly(acrylic acid)/calcium phosphate hybrid nanogels as pH-responsive drug carriers

Biocompatible, biodegradable and stimuli-responsive nanomaterials can be used as drug carriers and to achieve controlled drug delivery, which is crucial for treating tumors and lowering drug side effects. Calcium phosphate (CaP) nanoparticles and poly(acrylic acid) (PAA) hydrogels can be used as biocompatible and pH-responsive drug carriers. In this study, based on the ultrasound effect, PAA/CaP hybrid nanogels (approximately 100nm, PDI<0.2) are obtained via the cross-linking of CaP nanoparticles and PAA molecules between the Ca2+ ions and –COOH groups. The PAA/CaP hybrid nanogels show good stability in biological media as well as no hemolysis and no cytotoxicity to L02 cells. Moreover, the PAA/CaP hybrid nanogels display an enhanced loading capacity (approximately 32%) for doxorubicin hydrochloride (DOX) compared to pure CaP nanoparticles (approximately 7.5%) and a pH-controlled drug release due to their dissolution in acidic environment. DOX can be delivered into cancer cells by the PAA/CaP hybrid nanogels, which show an inhibitory effect comparable to that of free DOX, although the inhibitory effect is delayed due to the slow release of DOX from the carriers. In vivo, the PAA/CaP hybrid nanogels cannot avoid the capture by the reticuloendothelial system; however, they show passive tumor targeting ability. In brief, the biocompatible, biodegradable and pH-responsive PAA/CaP hybrid nanogels have the potential to act as drug carriers for controlled drug release.

Synthesis of multifunctional upconversion NMOFs for targeted antitumor drug delivery and imaging in triple negative breast cancer cells

Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 lacking triple negative breast cancers (TNBC) are the leading cause of death. The successful transport of chemotherapeutics in TNBC with receptor mediated targeting and image guided treatment is a serious challenge for cancer therapy. In this work, folic acid encapsulated nanoscale metal organic framework (NMOFs) is developed on the surface of upconversion nanoparticles (UCNPs) as a targeted and pH responsive anticancer drug carrier. To construct the assembled core-shell drug delivery system (DDS), NaYF4: Yb3+, Er3+ is taken as UCNPs for its outstanding luminescence properties, then a folic acid encapsulated NMOFs based on tetravalent metal Zr (IV) is directly developed on UCNPs [labeled as UCNP@UIO-66(NH2)/FA]. Excitingly, UCNP@UIO-66(NH2)/FA are nontoxic towards TNBC cells (MDA-MB-468) and normal cell lines (NIH3T3). The anticancer drug doxorubicin (DOX) is encapsulated into UCNP@UIO-66(NH2)/FA with high drug loading efficiency (1.42g DOX per g NMOFs) and shows pH responsive drug release. The DOX loaded UCNP@UIO-66(NH2)/FA successfully enters into the MDA-MB-468 cells through a folate receptor mediated endocytosis and exhibits a higher cytotoxicity than normal cells. Flow cytometry and nuclear apoptosis studies suggest the present DDS can be potential applicable in breast cancer therapy to reduce the side effects.

Microwave-assisted synthesis of thermo- and pH-responsive antitumor drug carrier through reversible addition–fragmentation chain transfer polymerization

Microwave-assisted synthesis of thermo- and pH-responsive antitumor drug carrier through reversible addition–fragmentation chain transfer polymerization

Facile synthesis of Prussian blue nanoparticles as pH-responsive drug carriers for combined photothermal-chemo treatment of cancer

Multifunctional PEGylated PB-DOX NPs with a lipid-PEG shell were developed as a gram-scale manner and used as novel pH-responsive drug delivery vehicles for combined photothermal-chemo treatment of cancer cells with high efficacy.

Mathematical Models for Controlled Drug Release Through pH-Responsive Polymeric Hydrogels

Hydrogels consisting of weakly charged acidic/basic groups are ideal candidates for carriers in oral delivery, as they swell in response to pH changes in the gastrointestinal tract, resulting in drug entrapment at low pH conditions of the stomach and drug release at high pH conditions of the intestine. We have developed 1-dimensional mathematical models to study the drug release behavior through pH-responsive hydrogels. Models are developed for 3 different cases that vary in the level of rigor, which together can be applied to predict both in vitro (drug release from carrier) and in vivo (drug concentration in the plasma) behavior of hydrogel-drug formulations. A detailed study of the effect of hydrogel and drug characteristics and physiological conditions is performed to gain a fundamental insight into the drug release behavior, which may be useful in the design of pH-responsive drug carriers. Finally, we describe a successful application of these models to predict both in vitro and in vivo behavior of docetaxel-loaded micelle in a pH-responsive hydrogel, as reported in a recent experimental study.

Analytical characteristics and application of novel chitosan coated magnetic nanoparticles as an efficient drug delivery system for ciprofloxacin. Enhanced drug release kinetics by low-frequency ultrasounds

A pH-responsive drug carrier based on chitosan coated iron oxide nanoparticles (CS-Fe3O4) for prolonged antibiotic release in a controlled manner is reported. As an antibiotic drug model, ciprofloxacin was loaded onto the nanocarrier via H-bonding interactions. The nanoparticles were characterized using scanning electron microscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, photon correlation spectroscopy and Fourier transform infrared spectroscopy. The particle size of CS-Fe3O4 nanoparticles were found to lie in the range of 30–80nm. The analytical characteristics of the designed system were thoroughly investigated. The in vitro drug loading at pH 4.8 and release kinetics at pH 7.4 studies revealed that the drug delivery system can take 99% of ciprofloxacin load and quantitatively release the drug over a sustained period of 5 days. The release kinetics study indicated that the system follows a zero order kinetics via a diffusion-controlled mechanism. These results indicated that CS-Fe3O4 nanoparticles have the potential for use as controlled antibiotic delivery systems through oral administration by avoiding the drug release in the highly acidic gastric fluid region of the stomach. Furthermore, the ability of low-frequency ultrasound in fast release of the encapsulated drug in less than 60min from the CS-Fe3O4 nanoparticles in a controlled manner was confirmed.

A porphyrin-based metal–organic framework as a pH-responsive drug carrier

A low cytotoxic porphyrin-based metal–organic framework (MOF) PCN-221, which exhibited high PC12 cell viability via 3-(4,5-dimethylthiazol-2-yl)−2,5-diphenyl tetrazolium (MTT) assay, was selected as an oral drug carrier. Methotrexate (MTX) was chosen as the model drug molecule which was absorbed into inner pores and channels of MOFs by diffusion. PCN-221 showed high drug loading and sustained release behavior under physiological environment without “burst effect”. The controlled pH-responsive release of drugs by PCN-221 revealed its promising application in oral drug delivery.

Ability to self-assemble of humic acids for production of pH responsive nanoparticles with antioxidant activity and capability for entrapping lipophilic compounds

Event Abstract Back to Event Ability to self-assemble of humic acids for production of pH responsive nanoparticles with antioxidant activity and capability for entrapping lipophilic compounds Maria Helena Santana1, Bruna Alice Melo1 and Fernanda Motta1 1 University of Campinas, Department of Materials Engineering and Bioprocesses, Brazil Humic acids (HAs) are macromolecules that comprise humic substances , which are distributed in terrestrial soil, natural water, and sediments, as a result of the decay of vegetable and natural residues . Commercial HAs are extracted from peat and coal. Recently, we demonstrated that HAs could be produced by fungal fermentation using the empty fruit bunch of palm trees as a natural sustainable source . The natural HAs have variable composition, depending on the source and extraction process. Their molecular structure contain numerous groups including carboxylic acid, phenol, enol, alcohol, quinone, ether and others, which grants them multiple functionalities. Natural HAs have been widely used in agriculture as nutrient and fungicidal and also to capture metals in soil and water. HAs also are beneficial to human health mainly as antioxidant, antiinflammatory and for wound healing. Furthermore, the natural muds containing HAS are used as thermal mud-packs in cosmetic treatments and also for alleviate the pain of joins in osteoarthritis. The sustainable and controlled production perspective opens ways for the development of new HAs-based products for pharmaceutical and medical applications. In this context, we explored the ability of HAs for pH-induced deprotonation/deprotonation as a strategy for the controlled production of colloidal nanoparticles, the incorporation of Pluronic 127 surfactant, and also the capabilities these structures as antioxidants and for entrapment of curcimun as a lipophilic compound. The results shown that pH–induced deprotonation/protonation produced nanoparticles with controlled size (100-200nm mean diameter) and zeta potential. Moreover, these structures were able to interact with Pluronic 127, forming flexible nanoparticles able to permeate nanoporous membranes, remaining their integrity. The antioxidant assays have showed that HAs were able to scavenge ABTS ( 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid), which was more effective in the presence of PF127. HAs also have shown efficiency higher than 90% for curcumin entrapment, increasing their antioxidant effects in a synergistic manner. These results points out for the feasibility of using HAs or HAs-PF127 nanoparticles in topical treatments as an antioxidant agent and/or as a lipophilic and pH-responsive drug carrier. Keywords: Drug delivery, nanoparticle, stimuli-response, biofunctional molecule Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016. Presentation Type: Poster Topic: Nano-structured materials for unique functions Citation: Santana M, Melo B and Motta F (2016). Ability to self-assemble of humic acids for production of pH responsive nanoparticles with antioxidant activity and capability for entrapping lipophilic compounds. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.02824 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 27 Mar 2016; Published Online: 30 Mar 2016. Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Maria Helena Santana Bruna Alice Melo Fernanda Motta Google Maria Helena Santana Bruna Alice Melo Fernanda Motta Google Scholar Maria Helena Santana Bruna Alice Melo Fernanda Motta PubMed Maria Helena Santana Bruna Alice Melo Fernanda Motta Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Synthesis of water-dispersible silicon-containing hydroxyapatite nanoparticles with adjustable degradation rates and their applications as pH-responsive drug carriers

An environmentally friendly method was developed to synthesize water-dispersible Si-HAp nanoparticles with adjustable degradation rates, high loading capacities for anticancer drugs, and sustained and pH-dependent drug release properties.

Calcite Single Crystals as Hosts for Atomic‐Scale Entrapment and Slow Release of Drugs

Doxorubicin (DOX)/CaCO3 single crystals act as pH responsive drug carrier. A biomimetic approach demonstrates that calcite single crystals are able, during their growth in the presence of doxorubicin, to entrap drug molecules inside their lattice along specific crystallographic directions. Alterations in lattice dimensions and microstructural parameters are determined by means of high-resolution synchrotron powder diffraction measurements. Confocal microscopy confirms that doxorubicin is uniformly embedded in the crystal and is not simply adsorbed on the crystal surface. A slow release of DOX was obtained preferentially in the proximity of the crystals, targeting cancer cells.

Dual-Responsive pH and Temperature Sensitive Nanoparticles Based on Methacrylic Acid and Di(ethylene glycol) Methyl Ether Methacrylate for the Triggered Release of Drugs.

A series of thermo-and pH-responsive poly(methyl methacrylate)-block-poly[methacrylic acid-co-di(ethylene glycol) methyl ether methacrylate] PMMA-b-P[MAA-co-DEGMA] block copolymers were synthesized by RAFT polymerization and self-assembled into micelles. The molar ratio of MAA was altered from 0-12% in order to modulate the lower critical solution temperature (LCST) of PDEGMA. The release of the drug albendazole from the micelle was strongly dependent on the temperature and the LCST value of the polymer. Systems below the LCST released the drug slowly while increasing the temperature above the LCST or decreasing the pH value to 5 resulted in the burst-like release of the drug. ABZ delivered in this pH-responsive drug carrier had a higher toxicity than the free drug or the drug delivered in a non-responsive drug carrier.

Multifunctional ultrasmall Pd nanosheets for enhanced near-infrared photothermal therapy and chemotherapy of cancer

Near-infrared (NIR) photothermal therapy has developed very quickly in recent years. However, its clinical applications are hindered by many practical problems, such as low accumulation in tumors, high laser power density and high biotoxicity in vivo. Herein, a versatile system combining chemotherapy with photothermal therapy for cancer therapy using ultrasmall Pd nanosheets (SPNS) has been developed. The SPNS can serve as pH-responsive drug carriers to efficiently deliver DOX into cancer cells and tumors. On the other hand, the coordinative loading of DOX on SPNS enhances its accumulation in tumor tissue. So we can efficiently ablate tumor using low-intensity laser radiation. Importantly, with ultrasmall size (∼4.4 nm), SPNS surface-functionalized with reduced glutathione (GSH) can be cleared from the body through the renal system into the urine. This cancer therapeutic nanosystem, which exhibits a significant synergistic effect and low systemic toxicity, has great potential for clinical applications.