pH-responsive Drug Delivery Research Articles

A Dual pH/Magnetic Responsive Nanocarrier Based on PEGylated Fe₃O₄ Nanoparticles for Doxorubicin Delivery.

Cancer chemotherapy has limitations such as nonselective distribution of drugs, detrimental side effects on normal tissues; here we reported a smart pH and magnetic sensitive drug delivery system (DDS) based on PEGylated Fe3O4 superparamagnetic nanoparticles. The citric-coated Fe3O4 (CIO) nanoparticles were firstly synthesized and further functionalized by biocompatible poly(ethylene glycol) bis(carboxymethyl ether) (COOH-PEG-COOH), thus PEGylated CIO (GCIO) nanoparticles were obtained. Doxorubicin (DOX) was conjugated as a model drug to the nanoparticles via hydrazone bond. The roughly sphere GCIO nanoparticles were comparatively strong magnetism with high drug loading capability (~89%) in relatively uniform size. Drug release study revealed that the GCIO-DOX performed pH-responsive drug-release properties. MTT assay demonstrated that GCIO nanoparticles possessed low cytotoxicity and good physiological stability. Further, cell viability results indicated that the GCIO-DOX showed effective cytotoxicity only a bit lower than free DOX. All obtained data indicated that the combined pH-responsive and magnetic multifunction drug delivery system can has excellent potential applications in cancer therapy.

Multicolor fluorescent carbon nanodots@zeolitic imidazolate framework-8 nanoparticles for simultaneous pH-responsive drug delivery and fluorescence imaging

Multicolor fluorescent carbon nanodots@zeolitic imidazolate framework-8 nanoparticles for simultaneous pH-responsive drug delivery and fluorescence imaging

PEG-dBSA-RuS1.7 Nanoclusters as a NIR Light and pH Responsive Drug Delivery Nanoplatform for Chemo-Photothermal Synergistic Therapy.

A combination of chemotherapy and photothermal therapy has emerged as a promising method of cancer treatment since it can enhance therapeutic efficacies and reduce side effects. Herein, we fabricated doxorubicin (DOX) loaded PEG-dBSA-RuS1.7 which could be used as a synergistic therapeutic nanoplatform. The PEG-dBSA-RuS1.7/DOX nanoparticles exhibit good monodispersity, physiological stability and biocompatibility. Moreover, the prepared PEG-dBSA-RuS1.7/DOX nanoparticles can intelligently release DOX by pH- and NIR-triggered therapy. In comparison with chemotherapy or photothermal treatment alone, the combined therapy shows a better therapeutic effect. We believe that the PEG-dBSA-RuS1.7/DOX can act as an efficient multifunctional nanoplatform for chemophotothermal synergistic cancer therapy.

Dual pH and glucose sensitive gel gated mesoporous silica nanoparticles for drug delivery

A low molecular weight gelator with dual pH and glucose sensitive moieties was synthesized. The gelator penetrated in the mesopores of silica nanoparticles (MSNs) and formed low molecular weight gel (LMWG) as gate to fabricate dual pH and glucose responsive nano drug delivery system. Antidiabetic drug was loaded in the gel caped MSNs, the drug release was responsive to the pH and glucose levels and the drug release could be controlled via the stimuli sensitivity of gel.

Novel pKa/DFT-Based Theoretical Model for Predicting the Drug Loading and Release of a pH-Responsive Drug Delivery System

Herein, we present a theoretical model that combines classical pKa theory with quantum mechanical calculations to predict the extent of interaction between acid-/base-dependent species over a full range of pH conditions. To demonstrate the theoretical model, we have predicted the drug loading and release of a pH-responsive drug delivery system consisting of sulfasalazine, an anionic anti-inflammatory drug molecule, loaded onto the positively charged trimethylammonium (TA)-functionalized mesoporous silica nanoparticle surface. The model relies on the possible combinations of pH-dependent states of the surface (S) and drug (D) molecules as neutral (0) and deprotonated (−1) states, whose relative probabilities depend on their pKa value and the desired pH. The four possible combinations were identified as S0D0, S0D–1, S–1D0, and S–1D–1, and periodic density functional theory calculations were performed for systems comprising drug fragments adsorbed onto a model TA-functionalized quartz surface to calculate th...

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.

Fluorescence-switchable ultrasmall fluorinated graphene oxide with high near-infrared absorption for controlled and targeted drug delivery

Although fluorinated graphene (FG) exhibits numerous excellent properties, its chemical inertness and hydrophobicity markedly limit its further application. Here, we report a novel strategy to synthesize nanosized water-soluble fluorinated graphene oxide (FGO) sheets that exhibit bright fluorescence (robust under both acidic and alkaline conditions), high near-infrared absorption and pH-responsive drug delivery. Structural adjustment of sizes into nanoscale (∼50 nm) endows FGO with superior photothermal performance surpasses those of FG and graphene oxide, and the fluorescence resonance energy transfer interactions between FGO and drugs allows switchable luminescence for monitoring the drug loading and release. The chemical introduction of oxygen facilitates the modification of FGO with folic acid for the first time and induces targeted endocytose into cancer cells. Enhanced hyperthermia, targeting specificity, and intracellular acid condition-triggered drug release guarantee the excellent therapeutic effects. Fine control over the structure and chemistry of FG, combined with high photoluminescence, enhanced photothermal effects, and targeted drug delivery makes our method potentially valuable in many fields.

Smart drug delivery systems based on nanoscale ZnO

In view of the excellent biocompatibility as well as the low cost, nanoscale ZnO shows great potential for drug delivery application. Moreover, The charming character enable nanoscale ZnO some excellent features (e.g. dissolution in acid, ultrasonic permeability, microwave absorbing, hydrophobic/hydrophilic transition). All of that make nanoscale ZnO reasonable choices for smart drug delivery. In the recent decade, more and more studies have focused on controlling the drug release behavior via smart drug delivery systems based on nanoscale ZnO responsive to some certain stimuli. Herein, we review the recent exciting progress on the pH-responsive, ultrasound-responsive, microwave-responsive and UV-responsive nanoscale ZnO-based drug delivery systems. A brief introduction of the drug controlled release behavior and its effect of the drug delivery systems is presented. The biocompatibility of nanoscale ZnO is also discussed. Moreover, its development prospect is looked forward.

A theranostic nanocomposite system based on iron oxide-drug nanocages for targeted magnetic field responsive chemotherapy

In this work, a theranostic nanocage system was developed for the targeted delivery of the anti-cancer agents camptothecin (CPT) and luotonin A (LuA). The core of the nanocage system (Fe3O4@OA-AD-SP NCs) was formed by biogenically synthesized Fe3O4 nanoparticles (NPs) decorated with a model anti-cancer drug (AD) and biosurfactant saponin (SP). The Fe3O4@OA-AD-SP NCs showed a high lipophilic AD loading efficiency (>80%) and a controlled pH-responsive drug release in stimulated cancerous cells in pH 6.4 media buffer. In addition, Fe3O4@OA-AD-SP NCs exhibited better serum protein binding efficacy at physiological pH values (7.4), furthering the important role of SP surface decoration. Particularly, these NCs showed better chemotherapeutic efficacy when examined in MCF-7 and HeLa cancer cell lines with a specific targeting capacity. Therefore, this study provides a new nano platform based on magnetic targeting and pH responsive lipophilic anticancer drug delivery to the cancer site.

Biocompatible, pH-responsive, and biodegradable polyurethanes as smart anti-cancer drug delivery carriers

In this study, biocompatible and biodegradable polyurethanes (PUs) were prepared by using different amino acids as chain extenders. Their structure and morphology were determined by fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis whereas their mechanical properties were evaluated by universal testing machine. These PUs were not only screened for their in vitro and in vivo cytotoxicity but also evaluated for their water uptake, swelling behavior, hydrolytic degradation and employed as pH-responsive drug delivery carriers. An anti-cancer drug imatinib was loaded to these PUs with 94% of loading efficiency and its release behavior was studied at different pH values. All the PUs showed a persistent local release for >300 h. The results exhibited that drug released at physiological pH (7.4) is far lesser as compared to the acidic and basic pH of the release media. At acidic pH, 82% of the drug has been released as compared to the 41% at physiological pH. The results clearly demonstrate that these PUs are safe and can be used as intelligent drug release matrices for targeted drug delivery.

Magnesium-Stabilized Multifunctional DNA Nanoparticles for Tumor-Targeted and pH-Responsive Drug Delivery.

Functional nucleic acids, which can target cancer cells and realize stimuli-responsive drug delivery in tumor microenvironment, have been widely applied for anticancer chemotherapy. At present, high cost, unsatisfactory biostability, and complicated fabrication process are the main limits for the development of DNA-based drug-delivery nanocarriers. Here, a doxorubicin (Dox)-delivery nanoparticle for tumor-targeting chemotherapy is developed taking advantage of rolling circle amplification (RCA) technique, by which a high quantity of functional DNAs can be efficiently collected. Furthermore, Mg2+, a major electrolyte in human body showing superior biocompatibility, can sufficiently condense the very long sequence of an RCA product and better preserve its functions. The resultant DNA nanoparticle exhibits a high biostability, making it a safe and ideal nanomaterial for in vivo application. Through cellular and in vivo experiments, we thoroughly demonstrate that this kind of Mg2+-stabilized multifunctional DNA nanoparticles can successfully realize tumor-targeted Dox delivery. Overall, exploiting RCA technique and Mg2+ condensation, this new strategy can fabricate nanoparticles with a nontoxic composition through a simple fabrication process and provides a good way to preserve and promote DNA functions, which will show a broad application potential in the biomedical field.

Controllable synthesis of up-conversion nanoparticles UCNPs@MIL-PEG for pH-responsive drug delivery and potential up-conversion luminescence/magnetic resonance dual-mode imaging

Rare-earth doped up-conversion nanoparticles (UCNPs) with high uniformity and dispersibility were synthesized by a facile solvothermal method. The conditions of synthesis for NaYF4:Yb/Tm were explored, and the NaYF4:Yb/Tm particles with the optimal size (about 300 nm) were obtained. Blue emission was observed with the excitation 980 nm near infrared (NIR) laser, indicating that the UCNPs can be potentially used for up-conversion luminescence (UCL) imaging. On basis of the optimal UCNPs, further coated by poly (ethylene glycol) (PEG) functionalized metal-organic frameworks (MOFs), a multifunctional platform UCNPs@MIL-PEG for cancer diagnosis and treatment was established. The core-shell structure was confirmed by TEM images. Doxorubicin (DOX) was selected as drug model and the drug loading of UCNPs@MIL-PEG was found to be 60%. Cytotoxicity indicated that UCNPs@MIL-PEG were highly biocompatible. The DOX release in different pH value revealed an excellent pH-triggered drug release. In addition, the UCNPs@MIL-PEG nanoparticles can be tracked by magnetic resonance imaging (MRI). A clear dose-dependent contrast enhancement in T2-weighted MR images indicated the potential act as T2 MRI contrast agents. The UCNPs@MIL-PEG nanoparticles are expected to be simultaneously used for UCL/MR dual-mode imaging and pH-responsive drug release.

Metal-Phenolic Encapsulated Mesoporous Silica Nanoparticles for pH-Responsive Drug Delivery and Magnetic Resonance Imaging

Abstract The anticancer drug doxorubicin (DOX) is locked in the mesoporous silica nanoparticle by coating FeIII-TA polymer, and its burst release can be achieved under acidic environment, along with the decreased longitudinal relaxivity. This nanoplatform shows great potential to monitoring the drug delivery process and the fate of the nanocarrier.

Hollow Mesoporous Silica@Metal-Organic Framework and Applications for pH-Responsive Drug Delivery.

Metal--organic frameworks (MOFs), a new type of porous crystalline material, hold great potential in biomedical applications, such as drug delivery. However, the efficacy of drug delivery is limited by low drug loading. In this work, we synthesized hollow mesoporous silica (HMS)@MOF capsules that can be used as a pH-responsive drug delivery system for the anticancer drug doxorubicin (DOX). DOX is loaded into the inner cavity of HMS. Zeolitic imidazolate framework-8 (ZIF-8) nanoparticles are then coated on the outer surface of the DOX-loaded HMS. The obtained material is a capsule (denoted as DOX/HMS@ZIF), in which DOX is encapsulated. The DOX/HMS@ZIF can be used as an efficient pH-responsive drug delivery system. DOX is not released under physiological conditions (pH 7.4), but is released at low pH (4-6) from DOX/HMS@ZIF. The DOX/HMS@ZIF capsule shows much higher cytotoxicity than free DOX and alters the delivery pathway for DOX in cancer cells, while the drug-free HMS@ZIF shows excellent biocompatibility. This opens new opportunities to construct a safe and efficient delivery system for targeted molecules using pH-responsive release for a wide range of applications.

Biocompatible and biodegradable zeolitic imidazolate framework/polydopamine nanocarriers for dual stimulus triggered tumor thermo-chemotherapy

Zeolitic imidazolate frameworks (ZIFs) have attracted great interest as pH-sensitive drug carrier because of high drug loading and intrinsic biodegradability. In this work, a biocompatible NIR and pH-responsive drug delivery nanoplatform based on ZIFs (PDA-PCM@ZIF-8/DOX) is synthesized for in vivo cancer therapy. The biocompatibility of ZIFs is greatly improved by polydopamine (PDA) modifying and proved by cytotoxicity and in vivo acute toxicity evaluation. The degradability is also regulated in an appropriate rate. Due to mild reaction condition of ZIFs, the synthesis and drug loading is achieved in one pot with high loading (37.86%) and encapsulation rate (78.76%). Meanwhile, PDA acts as a photothermal transfer agent to trigger thermal response switch of phase change materials for NIR controlled drug release. Under the dual stimulus of NIR and acid environment, the drug release is as high as 78%, while only 21% is released without stimulus, showing a remarkable effect of control release. In vivo anti-tumor experiments demonstrate the high tumor inhibition rate of photothermal-chemotherapy group with a significant synergistic effect. The biocompatible and biodegradable drug delivery platform based on ZIFs has shown great promise for future clinic cancer therapy.

Polyaspartic acid-anchored mesoporous silica nanoparticles for pH-responsive doxorubicin release.

BackgroundNanotechnology-based drug delivery systems exhibit promising therapeutic efficacy in cancer chemotherapy. However, ideal nano drug carriers are supposed to be sufficiently internalized into cancer cells and then release therapeutic cargoes in response to certain intracellular stimuli, which has never been an easy task to achieve.ObjectiveThis study is to design mesoporous silica nanoparticles (MSNs)-based pH-responsive nano drug delivery system that is effectively internalized into cancer cells and then release drug in response to lysosomal/endosomal acidified environment.MethodsWe synthesized MSNs by sol-gel method. Doxorubicin (DOX) was encapsulated into the pores as a model drug. Polyaspartic acid (PAsA) was anchored on the surface of mesoporous MSNs (P-MSNs) as a gatekeeper via amide linkage and endowed MSNs with positive charge.ResultsIn vitro release analysis demonstrated enhanced DOX release from DOX-loaded PAsA-anchored MSNs (DOX@P-MSNs) under endosomal/lysosomal acidic pH condition. Moreover, more DOX@P-MSNs were internalized into HepG2 cells than DOX-loaded MSNs (DOX@MSNs) and free DOX revealed by flow cytometry. Likewise, confocal microscopic images revealed that DOX@P-MSNs effectively released DOX and translocated to the nucleus. Much stronger cytotoxicity of DOX@P-MSNs against HepG2 cells was observed compared with DOX@MSNs and free DOX.ConclusionDOX@P-MSNs were successfully fabricated and achieved pH-responsive DOX release. We anticipated this nanotherapeutics might be suitable contenders for future in vivo cancer chemotherapeutic applications.

Construction of pH-responsive drug delivery platform with calcium carbonate microspheres induced by chitosan gels

Construction of simple and convenient platforms for controlled delivery of anti-cancer drugs is of great importance for medical science and pharmaceutics. Here, chitosan (CS) gels were used to induce the growth of calcium carbonate (CaCO3) microspheres, and the resulting CaCO3 microspheres were well dispersed within the three-dimensional (3D) network framework of the CS gels. The synthesized CaCO3/CS composites were then examined by field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), Fourier transform infrared spectrometry (FT-IR) and X-ray diffractometry (XRD). Finally, the designed CaCO3/CS composites were used for loading and controlled delivery of methotrexate (MTX), an anti-cancer drug. The encapsulation ratio of MTX calculated by UV–vis spectroscopy was approximately 78.8%. In addition, pH-responsive delivery of MTX from the CaCO3/CS composites was successfully achieved due to the pH-sensitive property of CS, and the cumulative release of MTX could reach 93.3%, 86.6% and 77.6% at pH 8.5, 7.4 and 5.8, respectively.

Smart Self-Assembled Nanosystem Based on Water-Soluble Pillararene and Rare-Earth-Doped Upconversion Nanoparticles for pH-Responsive Drug Delivery.

Exploring novel drug delivery systems with good stability and new structure to integrate pillararene and upconversion nanoparticles (UCNPs) into one system continues to be an important challenge. Herein, we report a novel preparation of a supramolecular upconversion nanosystem via the host-guest complexation based on carboxylate-based pillar[5]arene (WP5) and 15-carboxy-N,N,N-trialkylpentadecan-1-ammonium bromide (1)-functionalized UCNPs to produce WP5⊃1-UCNPs that can be loaded with the chemotherapeutic drug doxorubicin (DOX). Importantly, the WP5 on the surface of the drug-loaded nanosystem can be efficiently protonated under acidic conditions, resulting in the collapse of the nanosystem and drug release. Moreover, cellular uptake confirms that the nanosystem can enter human cervical cancer (HeLa) cells, resulting in drug accumulation in the cells. More importantly, cytotoxicity experiments demonstrated the excellent biocompatibility of WP5⊃1-UCNPs without loading DOX and that the nanosystem DOX-WP5⊃1-UCNPs exhibited an ability of killing HeLa cells effectively. We also investigated magnetic resonance imaging and upconversion luminescence imaging, which may be employed as visual imaging agents in cancer diagnosis and treatment. Thus, in the present work, we show a simple yet powerful strategy to combine UCNPs and pillar[5]arene to produce a unified nanosystem for dual-mode bioimaging-guided therapeutic applications.

Arginine-α, β-dehydrophenylalanine Dipeptide Nanoparticles for pH-Responsive Drug Delivery.

Nanoparticles (NPs) exhibiting responsiveness towards pH variations in organs, tissue microenvironments and cellular compartments can significantly add on to the drug delivery potential. Here, we have developed NPs from an amphipathic dipeptide, Arginine-α, β-dehydrophenylalanine (RΔF), and tried to explore their pH responsive drug delivery potential in various cancer cells. RΔF-NPs were architectured by harnessing the process of molecular self-assembly followed by the assessment of effect of pH on NPs morphology using zetasizer, SEM and CD. FTIR and PXRD analysis of the dipeptide and doxorubicin (Dox) were carried out for compatibility assessment followed by encapsulation of Dox in RΔF-NPs. RΔF-Dox-NPs were evaluated for pH dependent release as well as for in-vitro cellular internalization and efficacy in cancer cells. RΔF self-assembled to form monodispersed particles at pH7. SEM analysis revealed a loss of overall particle morphology along with particle aggregation at highly acidic and basic pH respectively. The NPs demonstrated a slow and sustained release behaviour at pH7 (97.64 ± 4.71% after 36h) in comparison to pH2 (90.27 ± 1.45% after 8h) and pH10 (96.39 ± 3.87% after 12h). In-vitro efficacy studies carried-out in various cancer cells revealed that RΔF-Dox-NPs exhibited higher efficacy with 1.65, 1.95 and 13.34 fold lower IC50 values in comparison to Dox in C6, HCT-116 and AGS cell lines. RΔF-Dox-NPs with higher drug release at acidic pH, enhanced internalization in cancer cells along with higher cytotoxic potential can act as effective pH responsive drug delivery systems.

Chemo-photothermal effects of doxorubicin/silica-carbon hollow spheres on liver cancer.

Chemo-photothermal therapy, which exhibits synergistic effects, is more effective than either of the treatments administered alone because of its superior ability to target and destroy cancer cells. An anti-cancer compound (doxorubicin, DOX) was embedded in silica–carbon hollow spheres (SCHSs) using heat and vacuum to integrate multi-therapeutic effects onto one platform and subsequently improve the anti-cancer efficacy. SCHSs were synthesized via a surface activation method and its highly porous surface enhanced the loading content of the desired drug. SCHSs are an infrared photothermal material that can destroy targeted cells by heating under near-infrared (NIR) laser illumination at 808 nm. NIR laser illumination also enhances DOX release from SCHSs to increase the anti-cancer efficiency of DOX–loaded SCHSs (DOX–SCHSs) in both two-dimensional and three-dimensional multicellular tumor spheroid cultures. SCHSs exhibited high heat-generating ability and pH-responsive drug delivery. In conclusion, this study demonstrated that DOX–SCHSs represent a potential tool for chemo-photothermal therapy due to its photothermal effects. Thus, our findings imply that the high cancer cell killing efficiency of DOX–SCHSs induced by NIR illumination can be used for the treatment of tumors.