pH-controlled Drug Delivery Research Articles

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.

Combinatory Cancer Therapeutics with Nanoceria-Capped Mesoporous Silica Nanocarriers through pH-triggered Drug Release and Redox Activity

In the field of nanomedicine, drug-loaded nanocarriers that integrate nanotechnology and chemotherapeutics are widely used to achieve synergistic therapeutic effects. Here, we prepared mesoporous silica nanoparticles capped with cerium oxide nanoparticles (COP@MSN) wherein a pH trigger-responsive mechanism was used to control drug release and intracellular drug delivery. We blocked the mesopores of the carboxyl-functionalized MSN with aminated COP. These pores could be opened in acidic conditions to release the loaded drug, thus establishing a pH-responsive drug release system. We loaded doxorubicin (DOX) as anticancer biomolecule into the pores of MSN and capped with COP. The COP@DOX-MSN system showed a typical drug release profile in an acidic medium, which, however, was not observed in a neutral medium. In vitro studies using cancer cell line (HeLa) proved that the COP@DOX-MSN entered efficiently into HeLa cells and released DOX to the level sufficient for cytotoxicity. The cytotoxic effect of COP in cancer cells was facilitated by the pro-oxidant property of COPs, which considerably raised the reactive oxygen species (ROS) level, thereby leading to cellular apoptosis. The combination of DOX with COP (COP@DOX-MSN) showed even higher ROS level, demonstrating a cytotoxic synergism of drug and nanoparticle in terms of ROS generation. Collectively, the COP@DOX-MSN is considered useful for cancer treatment with the combined capacity of pH-controlled drug delivery, chemotherapeutics, and redox activity.

RETRACTED ARTICLE: A Low Cytotoxic Metal–Organic Framework Carrier: pH-Responsive 5-Fluorouracil Delivery and Anti-Cervical Cancer Activity Evaluation

A new porous metal–organic framework (MOF) [Zn2(ad)2(fmdb)(H2O)](DMF)3 (1, DMF = N,N-dimethylformamide) based on zinc(II) ions, biomolecular adenine (Had) and 4,4′-(fluoromethylene)dibenzoic acid (H2fmdb) has been successfully obtained via a one-pot solvothermal reaction. The structural analysis via the single crystal X-ray diffraction reveals that compound 1 locates in the monoclinic space group C2/c and demonstrates a three-dimensional channel-type neutral framework. The as-prepared complex 1 exhibits low toxicity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium (MTT) assay, revealing its potential application in human health care. In light of its nano-sized channel space and good stability in biological buffers solution, the activated compound 1 (1a) has been applied as a carrier for loading the anticancer drug 5-Fu (5-Fluorouracil) though a simple adsorption process. The successful loading of 5-Fu was confirmed by the gas sorption measurement and the loading capacity was determined by UV–Vis spectroscopy, which reveals a drug loading capacity of 44.6 wt%. The drug delivery in the simulated cancerous tissues (pH = 5.0) exhibited a more complete release in comparison with that in the normal tissues (pH = 7.4), demonstrating the compound 1a could be potentially used as a pH-controlled drug delivery carrier. In connection to these, in vitro anticancer activity of 5-Fu loaded 1a was also evaluated using MTT assays against two human cervical cancer cells HeLa and SiHa.

The Fabrication of rGO/(PLL/PASP)3 @DOX Nanorods with pH-Switch for Photothermal Therapy and Chemotherapy.

The development of well-controlled drug carriers that are stable and highly effective for the delivery of anticancer agents is challenging. Herein, we report a novel pH-controlled drug delivery system, utilizing reducing graphene oxide (rGO)-polymer self-assembly films as carriers, for the preparation of effective drug nanorods and nanoparticles. In this system, the rGO-polymer carriers were constructed by the alternating assembly of poly-l-lysine (PLL) and polyaspartic acid (PASP) around the rGO sheets. Furthermore, the rGO-polymer cores, which possess a positively charged surface as the desired template, could assemble with negatively charged doxorubicin (DOX) via electrostatic interactions. The DOX embedding efficiency and the morphology of the drug nanocomposites could be controlled by the number of rGO-polymer bilayers and concentration of the rGO-polymer bilayers and the initial DOX concentration. Importantly, the release of DOX could be regulated by controlling the pH and by using a NIR laser. Under acidic conditions, the interactions between the PASP layer and DOX molecules can be broken, resulting in gradual release of the DOX molecules. Upon NIR irradiation, the release of DOX could be further accelerated and a photothermal effect from rGO induced. Cellular uptake and cytotoxicity experiments indicate that the drug nanocomposites possess effective anticancer activity. Thus, in this work, we present a useful strategy for the fabrication of pH-responsive drug nanocomposites for combined photothermal and chemical therapy. The nanocomposite can be used as a potential drug delivery system for practical cancer treatment.

A Biocompatible Ti-based metal-organic framework for pH responsive drug delivery

A biocompatible Ti-based metal-organic framework (MOF) MIL-125 (MIL stands for Materials of Institut Lavoisier) was explored as a potential pH-controlled drug delivery carrier which promoting drug release in acidic conditions without any tedious post-modification. The mechanism of the pH-responsive drug delivery was attributed to the different stability of MIL-125. Its good biocompatibility was further demonstrated by the in vitro results via MTT assay and confocal microscopy images.

Hydrazone-Containing Triblock Copolymeric Micelles for pH-Controlled Drug Delivery.

In this study, the structure–activity relationship of amphiphilic block copolymer micelles as nanosized drug delivery system was revealed. Firstly, a biodegradable triblock polymers PEG-DiHyd-PLA containing hydrazone bond was synthesized through the ring-opening polymerization. In this method, PEG-DiHyd-Phenol was used as the initiator and L-lactide as the monomer. Then, the polymeric micelles were formed and used as nano-drug carriers with pH sensitivity. The structure and composition of the polymer were characterized by infrared (IR), nuclear magnetic resonance (1H-NMR), and gel permeation chromatography (GPC), we characterized the self-assembling process of the triblock polymers and the pH sensitivity of the micelles by the means of transmission electron microscopy (TEM), dynamic light scattering method (DLS). Doxorubicin (DOX) acts as the model drug, and we researched the capacities of drug loading and release in vitro of the micelles. MTT experiments showed that the blank micelles of PEG-DiHyd-PLA were not cytotoxic to tumor cells (HepG-2, MCF-7) and normal cell (L-02 cells), but the DOX loaded ones displayed more toxicity than the ones without hydrazone, which was consistent to the further confocal laser scanning microscopy and flow cytometry study.

PH-Controlled drug delivery with hybrid aerogel of chitosan, carboxymethyl cellulose and graphene oxide as the carrier

Hybrid aerogels of chitosan (CS), carboxymethyl cellulose (CMC) and graphene oxide (GO) are successfully prepared by using calcium ion (Ca2+) as the crosslinker. The resultant hybrid aerogels, CS/CMC/Ca2+/GO, are characterized by field emission scanning electron microscopy (FESEM) and Fourier transform infrared (FT-IR) spectroscopy. Due to the pH sensitivity of CS and CMC, pH-controlled drug delivery with CS/CMC/Ca2+/GO as the carrier is investigated using 5-fluorouracil (5-FU), an effective chemotherapeutic agent in the treatment of cancers, as the model drug. Finally, Higuchi model and Korsmeyer-Peppas model are used to study the release kinetics, and it reveals that the release of 5-FU from the hybrid aerogels is controlled by Fickian diffusion. Collectively, the findings demonstrate the CS/CMC/Ca2+/GO would be a potential material for the construction of pH-controlled drug delivery platform.

Construction of poly (vinyl alcohol)/poly (lactide-glycolide acid)/vancomycin nanoparticles on titanium for enhancing the surface self-antibacterial activity and cytocompatibility

Comparing with traditional drug dosage form, controlled release systems offer more effective and favorable route to deliver drugs in optimum dose to specific sites with long term release duration. In this work, an effective drug delivery system composed of poly (vinyl alcohol) (PVA)/poly (lactide-glycolide acid) (PLGA) nanoparticles (NPs) with encapsulated vancomycin (Van), is constructed on the surface of biomedical titanium. The PVA/PLGA/Van NPs synthesized via double emulsion route are grafted onto the surface of titanium plates modified by alkaline-heat treatment and subsequent aminopropyltriethoxysilane (APTES) deposition. In vitro tests disclose that NPs can release a small amount of drugs continuously due to the slow swelling or hydrolysis of polymer chain segments as the immersion time increases. As the pH value reduces, the ester bonds rupture with releasing more drugs, which is why this drug delivery system exhibits the highest antibacterial efficiency at the lowest pH value of 4.5 in this work. Cell culture results reveal that this smart surface system on titanium facilitates the cell attachment and proliferation on implants. Hence, this pH controlled drug delivery system can be successfully applied as a bio-platform for improving both the osteoblasts adhesion and antibacterial activity of metallic implants.

A Computational/Experimental Assessment of Antitumor Activity of Polymer Nanoassemblies for pH-Controlled Drug Delivery to Primary and Metastatic Tumors.

Polymer nanoassemblies (PNAs) with drug release fine-tuned to occur in acidic tumor regions (pH < 7) while sparing normal tissues (pH = 7.4) were previously shown to hold promise as nanoparticle drug carriers to effectively suppress tumor growth with reduced systemic toxicity. However, therapeutic benefits of pH-controlled drug delivery remain elusive due to complex interactions between the drug carriers, tumor cells with varying drug sensitivity, and the tumor microenvironment. We implement a combined computational and experimental approach to evaluate the in vivo antitumor activity of acid-sensitive PNAs controlling drug release in pH5 ~ 7.4 at different rates [PNA1 (fastest) > PNA2 > PNA3 (slowest)]. Computational simulations projecting the transport, drug release, and antitumor activity of PNAs in primary and metastatic tumor models of colorectal cancer correspond well with experimental observations in vivo. The simulations also reveal that all PNAs could reach peak drug concentrations in tumors at 11h post injection, while PNAs with slower drug release (PNA2 and PNA3) reduced tumor size more effectively than fast drug releasing PNA1 (24.5 and 20.3 vs 7.5%, respectively, as fraction of untreated control). A combined computational/experimental approach may help to evaluate pH-controlled drug delivery targeting aggressive tumors that have substantial acidity.

Coadsorption of Doxorubicin and Selected Dyes on Carbon Nanotubes. Theoretical Investigation of Potential Application as a pH-Controlled Drug Delivery System.

This work shows results of a theoretical survey, based on molecular dynamics simulation, of potential applicability of doxorubicin coadsorption with various dyes molecules on/in carbon nanotubes as a drug delivery system. The central idea is to take advantage of the dyes charge distribution change upon switching the pH of the environment from neutral (physiological 7.4) to acidic one (∼5.5 which is typical for tumor tissues). This work discusses results obtained for four dye molecules revealing more or less interesting behavior. These were bromothymol blue, methyl red, neutral red, and p-phenylenediamine. All of them reveal pKa in the range 5-7 and thus will undergo protonation in that pH range. We considered coadsorption on external walls of carbon nanotubes and sequential filling of the nanotubes inner hollow space by drug and dyes. The latter approach, with the application of neutral red and p-phenylenediamine as blockers of doxorubicin, led to the most promising results. Closer analysis of these systems allowed us to state that neutral red can be particularly useful as a long-term blocker of doxorubicin encapsulated in the inner cavity of (30,0) carbon nanotube at neutral pH. At acidic pH we observed a spontaneous release of neutral red from the nanotube and unblocking of doxorubicin. We also confirmed, by analysis of free energy profiles, that unblocked doxorubicin can spontaneously leave the nanotube interior at the considered conditions. Thus, that system can realize pH controlled doxorubicin release in acidic environment of tumor tissues.

Construction of site-specific core–shell structured nanocomposite for pH-controlled drug delivery

In this study, a pH-controlled core–shell structured site-specific magnetic nanocomposite for drug delivery was reported. Superparamagnetic Fe3O4 nanoparticles were selected to build its core for magnetic guiding purpose and mesoporous silica molecular sieve MCM-41 was chosen to construct its outer shell. The MCM-41 outer shell has highly ordered hexagonal tunnels therefore would offered enough cargo space for drug molecules. An organic ligand N1-(5H-cyclopenta[1,2-b:5,4-b′]dipyridin-5-ylidene)benzene-1,4-diamine (denoted as Dafo-Ph-NH2) was linked to the molecular sieve outer shell. There are two nitrogen atoms at the end of the ligand which are able to donate their lone pair electrons. Acidic drug molecules therefore can be bound to the ligand via weak acid–base reaction. Those drug molecules can be release in low pH solution since the H+ in the solution will compete with the ligand. The final composite was analyzed by electron microscope images, XRD, IR spectra, thermogravimetry and N2 adsorption/desorption. Its bio-compatibility was evaluated by MTT using L929 fibroblast cell line. Our Dafo-MCM-41@Fe3O4 composite shows pH-controlled and site-specific smart release properties for aspirin in vitro.

PH-responsive ibuprofen delivery in silane-modified poly(methylacrylic acid) coated bimodal mesoporous silicas

A facile grafting-onto strategy has been exploited to prepare a smart pH-controlled drug delivery system (P–B) via surface-grafting of the preformed silane modified with PMAA [poly(methylacrylic acid)] onto the surface of BMMs (bimodal mesoporous silicas). Accordingly, the PMAA acted as the pH-sensitive component, and the silane provided an anchor with the surface OH group of BMMs. Thereby, a series of P–B with different mass ratio of BMMs to PMAA have been synthesized. Meanwhile, ibuprofen (IBU) was applied as a model drug to investigate the influences of different pH values on drug release. The results showed that the obtained P–B presented a flexible control over drug release by adjusting the grafted amount of PMAA. Moreover, the drug release amount of the drug-loaded samples was pH dependent and increased with the increasing of pH value, implying that the P–B are promising drug-carriers in application of pH-responsive controlled drug delivery systems.

PH controlled release anticancer drug delivery based on poly(A)/SiO&amp;lt;sub&amp;gt;2&amp;lt;/sub&amp;gt; nanoparticles

利用异喹啉类生物碱小分子化合物与腺嘌呤（A碱基）在酸性条件结合力下降的特点，以具有良好生物相容性、DNA酶切保护性以及易于生物修饰的二氧化硅纳米颗粒为载体，发展了一种基于聚A链（Poly（A））/二氧化硅纳米颗粒（Poly（A）/SiNPs）的pH可控释放抗肿瘤药物体系. 在该体系中，选择了甲氧檗因（coralyne）作为药物模式分子，通过共价修饰方法在二氧化硅纳米颗粒表面修饰Poly（A），获得Poly（A）/SiNPs颗粒，通过A碱基-甲氧檗因-A碱基结合方式构建了甲氧檗因载药体系. 采用琼脂糖凝胶电泳、透射电子显微镜以及荧光光谱等方法对载药体系进行了表征，考察了载药体系的稳定性和在不同pH缓冲液中的释放情况，并采用激光共聚焦成像技术和MTT方法分别考察了该体系在Hela细胞内的定位以及杀伤效果. 结果表明：Poly（A）被成功修饰在二氧化硅纳米颗粒上后能很好地与甲氧檗因结合，构建甲氧檗因载药体系，该体系在中性条件具有较好的稳定性，而在酸性条件下（pH

PH-sensitive poly(glutamic acid) grafted mesoporous silica nanoparticles for drug delivery

pH-sensitive poly(L-glutamic acid) grafted mesoporous silica nanoparticles (MSN-PLGA) were prepared by the surface-initiated N-carboxyanhydride polymerization method. The resultant MSN-PLGA was well dispersed in aqueous medium and showed high drug loading efficiency, superior stability, and significantly higher drug release rates. The cumulative release of doxorubicin hydrochloride (DOX) from DOX-loaded MSN-PLGA (DOX@MSN-PLGA) was pH-dependent and the release rate was much higher at pH 5.5 than that at pH 7.4. The cytotoxicity results indicated that the blank MSN-PLGA was biocompatible and the DOX@MSN-PLGA had potent in vitro cytotoxicity effect similar to free DOX. Overall, these results demonstrate that MSN-PLGA is a promising platform to build pH controlled drug delivery systems for cancer therapy.

Encapsulation of an Adamantane-Doxorubicin Prodrug in pH-Responsive Polysaccharide Capsules for Controlled Release

Supramolecular microcapsules (SMCs) with the drug-loaded wall layers for pH-controlled drug delivery were designed and prepared. By using layer-by-layer (LbL) technique, the SMCs were constructed based on the self-assembly between polyaldenhyde dextran-graft-adamantane (PAD-g-AD) and carboxymethyl dextran-graft-β-CD (CMD-g-β-CD) on CaCO(3) particles via host-guest interaction. Simultaneously, adamantine-modified doxorubicin (AD-Dox) was also loaded on the LbL wall via host-guest interaction. The in vitro drug release study was carried out at different pHs. Because the AD groups were linked with PAD (PAD-g-AD) or Dox (AD-Dox) by pH-cleavable hydrazone bonds, AD moieties can be removed under the weak acidic condition, leading to destruction of SMCs and release of Dox. The pH-controlled drug release can enhance the uptake by tumor cells and thus achieve improved cancer therapy efficiency.

PH-controlled delivery of gentamicin sulfate from orthopedic devices preventing nosocomial infections

Since the beginning of the 1970s, controlled release technology has witnessed great advancement, and motivated numerous researchers in materials science. These systems overcome the drawbacks of traditional drug dosage form, and offer more effective and favorable methods to optimize drug delivery in optimum dose to specific sites or to prolong delivery duration. This paper deals with the synthesis of pH-controlled drug delivery systems for bone implant, allowing the local release of gentamicin sulfate (GS), an antibiotic commonly used to prevent infections during orthopedic surgeries. We present a biomaterial synthesis allowing the controlled release of GS at the site of surgical implantation (over an adjustable period of time). In our design, spherical nanoparticles (NPs) functionalized by the chosen antibiotic (Gentamicin sulfate, GS), are chemically anchored to the biomaterial surface. A cleavage reaction of the chemical bond between NPs and GS, effected by the contact of material with a solution presenting an acidic pH (in the case of infection, there is a decrease of the physiological medium pH), induces controlled release of the bioactive molecule in its native form.In this paper, we discuss the synthesis of a bioactive titanium based biomaterial in general, and the grafting of the NPs onto the titanium surfaces in particular. We have paid particular attention to the characterization of the drug surface density and the release kinetic of the active molecule as a function of the pH. In vitro bacterial growth inhibition tests after GS delivery at acidic pH (with Staphylococcus aureus) have also been carried out in order to prove the efficiency of such biomaterials.

Controlled Release and Assembly of Drug Nanoparticles via pH-Responsive Polymeric Micelles: A Theoretical Study

Tumor tissues often have a pH value lower than normal tissues, and this difference suggests a promising way of targeted cancer therapy by using pH-controlled drug delivery systems. On the basis of the mean-field theory, we present a theoretical methodology to predict the self-assembly and disassembly of pH-responsive polymers and nanoparticles in an ionic solution. It is found that vesicles, cylindrical, and spherical micelles can rapidly disassemble and release contained nanoparticles in a narrow pH range. The model is further used to study the controlled assembly of pH-sensitive drug with significantly improved encapsulation efficiency. This method is also applicable for the design of controlled delivery nanodevices for various biomedical applications.

Entrapped polyamines in biomimetically synthesized nanostructured silica spheres as pH-responsive gates for controlled drug release

We report here a versatile pH-controlled drug delivery system utilizing the polyamine-mediated bio-inspired mineralization approach. In a single step method suitably functionalized monodisperse mesoporous silica spheres (MMS) are obtained, which when encapsulated with ibuprofen, a nonsteroidal anti-inflammatory drug, lead to pH-responsive controlled release of the drug from the mesoporous channels. The polyamines that are responsible for the silicification process in turn act as molecular gates controlling the drug release in a pH dependent manner. Interestingly, while the presence of a polyamine prevents the drug from releasing out of the pores, its absence in MMS allows the drug to be released at a neutral pH.

Cholic acids/salts as barriers to diffusing species: effect of pH.

Bile acids have been absorbed on a microporous polypropylene membrane and the diffusion of ionic and non-ionic compounds through the barriers obtained has been studied at different pH values. Results indicate that permeation rates are affected by environmental pH conditions and an explanation of this behaviour is proposed. This study represents an approach for a pH-controlled drug delivery system.

A possible pH-controlled drug delivery system based on a derivative of the polysaccharide scleroglucan.

Four carboxylated derivatives of scleroglucan have been obtained by oxidation, to different extents, of the glucopyranose side chains of the natural polysaccharide. The diffusion of model molecules through aqueous solutions of these new products was measured at various pH values. The reversible pH induced sol-gel transition of some of the polyelectrolyte solutions tested effects a remarkable variation in the diffusion rate of the permeating species; in this sense the most interesting polysaccharide appears to be the product with 70% oxidized glucopyranose moieties. The behaviour of scleroglucan and its derivatives has been compared with that of carboxymethylcellulose and the mechanism involved in drug permeation and release discussed. The possible application of one of the new products in controlled release formulations for oral use is also reported.