pH-responsive Drug Delivery Research Articles

PH-sensitive polymeric nanocarriers for antitumor biotherapeutic molecules targeting delivery

pH-sensitive smart polymeric nanocarriers have been under development in the field of biomedicine due to permeabilization the physiological barriers readily to address the limitation of conventional chemotherapeutics delivery systems of low intracellular transport and targeting efficiency. Where traditional polymers kept stable under physiological neutral or acidic conditions, pH-sensitive polymeric nanocarriers underwent rapid degradation with a labile group in tumor acidic environment (around 5.0–6.0), allowing these biomaterials to achieve controlled drug release, drug pharmacokinetics improvement and antitumor biotherapeutic molecules efficiency enhancement compared with traditional polymers. This review mainly concentrated on properties of pH-sensitive polymers for biomedical purposes to construct the smart drug delivery system based on acid liable linkers which were categorized into pH-sensitive polymeric prodrugs composed of antitumor drugs (doxorubicin and paclitaxel) bounded to the polymer via acid liable linkers and pH-sensitive copolymeric nanocarriers prepared by block copolymers containing polymer blocks linked with acid-cleavable groups. Besides, advanced platforms in biomedicine for special biotherapeutic molecules delivery were reviewed in the article. Furthermore, several acid-sensitive linkages were reviewed to study the mechanism of the controlled pH-responsive drug delivery, such as hydrazone, acetal, cis-aconityl linker and β-thioether ester, as well as improvement of drug pharmacokinetics.

Selenium nanoparticles coated with pH responsive silk fibroin complex for fingolimod release and enhanced targeting in thyroid cancer

Cancer-targeted drug delivery systems based on nanoparticles (NPs) have been considered promising therapies. In this study, we developed a pH-responsive smart NPs drug delivery system using silk fibroin (SF), selenium nanoparticles (Se NPs), fingolimod (FTY720), and heptapeptide (T7). The prepared FTY720@T7-SF-Se NPs were spheres with an average diameter of 120 nm, which would contribute to the enhanced permeability and retention effects in tumour regions. The encapsulation efficiency (EE) of the FTY720@T7-SF-Se NPs was 71.95 ± 3.81%. The release of FTY720 from the nanocarriers was pH-dependent, and the release of FTY720 was accelerated in an acidic environment. Both in vitro and in vivo studies showed that FTY720@T7-SF-Se NPs had an enhanced cellular uptake selectivity and antitumor activity for thyroid cancer. The bio-distribution study in vivo further demonstrated that FTY720@T7-SF-Se NPs could effectively accumulate in the tumour region, thereby enhancing the ability to kill cancer cells in vivo. In addition, studies of histology and immunohistochemistry showed that FTY720@T7-SF-Se NPs had low toxicity to the major organs of tumour-bearing mice, indicating the prepared NPs has good biocompatibility in vivo. These results suggest that the tumour-targeted NPs delivery system (FTY720@T7-SF-Se NPs) has great potential as a new tool for thyroid cancer therapy.

Two-Photon Excitable Membrane Targeting Polyphenolic Carbon Dots for Long-Term Imaging and pH-Responsive Chemotherapeutic Drug Delivery for Synergistic Tumor Therapy

Two-Photon Excitable Membrane Targeting Polyphenolic Carbon Dots for Long-Term Imaging and pH-Responsive Chemotherapeutic Drug Delivery for Synergistic Tumor Therapy

Ultra-thin metal-organic framework nanosheets for chemo-photodynamic synergistic therapy.

Synergistic therapies, such as chemo-photodynamic therapy, have been growing fast because of their efficacy against cancers. Although metal-organic frameworks have been widely studied in the field of drug delivery, the metal-organic frameworks (MOFs) with a two-dimensional (2D) structure integrated by photosensitizers are rarely reported. However, chemo-photodynamic therapy still has limitations such as the inhibitory effect from intracellular glutathione (GSH). In this work, a simple bottom-up synthesis method was used to synthesize a pH-responsive drug delivery system with a 2D MOF structure. In particular, tetracarboxyporphyrin (TCPP) derivatives were coordinated with bivalent copper ions as organic bridging molecules in a polyvinylpyrrolidone (PVP) solution, and copper porphyrin MOFs (Cu-TCPP nanosheets) were synthesized by a hydrothermal method from bottom to top. DOX was loaded onto Cu-TCPP nanosheets by π-π stacking with a high drug loading rate of 33%. DOX@Cu-TCPP nanosheets showed pH-responsive DOX releasing behaviour and significant GSH scavenging ability. In addition, the evaluation of in vitro and in vivo treatment showed that DOX@Cu-TCPP nanosheets had high anti-tumor activity and excellent biocompatibility. Therefore, this study opens a new idea for the application of MOF nanosheets in tumor therapy and provides a supporting basis for the treatment of cancers by chemo-photodynamic synergistic therapy.

Co-delivery of autophagy inhibitor and gemcitabine using a pH-activatable core-shell nanobomb inhibits pancreatic cancer progression and metastasis.

Background: Metastasis is one of the main reasons for the high mortality associated with pancreatic ductal adenocarcinoma (PDAC), and autophagy regulates the metastatic migration of tumor cells, their invasion of tissues, and their formation of focal adhesions. Inhibiting autophagy may suppress tumor growth and metastasis, but the abundant extracellular matrix hinders the deep penetration of therapeutic agents.Methods: To enhance the penetration of drugs that can inhibit metastasis of pancreatic cancer, a pH-responsive drug delivery system was formulated. Gemcitabine (GEM), a first-line chemotherapeutic drug against PDAC, was loaded in 6PA-modified DGL (PDGL) nanoparticles to afford PDGL-GEM. Then PDGL-GEM was co-precipitated with the autophagy inhibitor chloroquine phosphate (CQ) and calcium phosphate to formulate PDGL-GEM@CAP/CQ. The size and morphology of the resulting “nanobomb” PDGL-GEM@CAP/CQ were characterized, and their uptake into cells, cytotoxicity and ability to inhibit autophagy were analyzed at pH 6.5 and 7.4. The anti-tumor and anti-metastasis effects of the nanobomb were explored on mice carrying Pan 02 pancreatic tumor xenografts or orthotopic tumors.Results: The pH-induced dissolution of calcium phosphate facilitated the release of CQ from the nanobomb and deep penetration of PDGL-GEM. The internalization of PDGL-GEM and subsequent intracellular release of GEM inhibited tumor growth, while CQ downregulated autophagy in tumor cells and fibroblasts. In fact, inhibition of xenograft and orthotopic tumor growth was greater with the complete PDGL-GEM@CAP/CQ than with subassemblies lacking GEM or CQ. More importantly, mechanistic studies in vitro and in vivo suggested that the nanobomb inhibits metastasis by downregulating MMP-2 and paxillin, as well as reducing fibrosis.Conclusion: The pH-sensitive PDGL-GEM@CAP/CQ shows potential for inhibiting proliferation and metastasis of pancreatic cancer through an autophagy-dependent pathway.

Ethidium bromide-bridged mesoporous silica hybrid nanocarriers for fluorescence cell imaging and drug delivery applications

We report the fabrication of mesoporous organosilica hybrid nanocarriers with red-fluorescence behaviour under UV-light for pH-responsive drug delivery and red-fluorescence-based bioimaging applications in cancer therapy.

The Design of Temperature and pH-Responsive Drug Delivery System Based on Cellulose and Aminated Cellulose by Computational and Experimental Methods

In this study, molecular dynamics (MD) simulations were performed on cellulose and aminated cellulose. Obtained results show the presence of amine moieties and their protonation, positive charges and repulsive forces increase. As a result, the van der Waals and electrostatic interactions and hydrogen bonding number decrease. Then, paclitaxel was loaded through docking into the structures and was studied by MD simulations. The simulations were performed in several protonation states along with 25∘C, 37∘C, 42∘C and 50∘C temperatures. The carrier/ligand system behaviors were analyzed. The results indicate the increase of temperature and protonation decrease hydrogen bonding number between drug and carrier and increase binding free energy. At last, to compare the simulations results, paclitaxel was loaded in cellulose and aminated cellulose and investigated in the in vitro release at two conditions (37∘C, pH 7.4, and 42∘C, pH 5). Experimental results prove computational results as pH/temperature-responsive system.

Anticancer Drug Release System Based on Hollow Silica Nanocarriers Triggered by Tumor Cellular Microenvironments.

Targeted release of anticancer drugs to tumor sites has a pivotal role in clinical oncology. pH-responsive drug delivery systems, with an intelligent and targeted release of anticancer drugs in a controllable manner based on sensitivities to the weakly acidic environments of tumor cellular microenvironments, are desirable. Herein, the design of such a pH-responsive drug delivery system is detailed using in situ amino-functionalized hollow mesoporous silica nanoparticles as carriers. The drug release behavior of the pH-responsive delivery system was evaluated under an in vitro simulation of tumor cellular microenvironments. The drug delivery system has efficient drug loadings and targeted release. Zorubicin hydrochloride releasing percentage is almost up to 100% at a buffer pH of 5.0. The drug release systems described demonstrating great potential in anticancer therapy.

Glucosamine-conjugated graphene quantum dots as versatile and pH-sensitive nanocarriers for enhanced delivery of curcumin targeting to breast cancer

Applying multifunctional nanocarriers, comprising specifically traceable and tumor targeting moieties, has significantly increased in cancer theranostics. Herein, a novel targeted, trackable, and pH-responsive drug delivery system was fabricated based on glucosamine (GlcN) conjugated graphene quantum dots (GQDs) loaded by hydrophobic anticancer agent, curcumin (Cur), to evaluate its targeting and cytotoxicity potential against breast cancer cells with overexpression of GlcN receptors. The biocompatible photoluminescent GQDs were synthesized from graphene oxide through the green and facile oxidizing method. The structural and spectral characterizations of the as-prepared GQDs and Cur/GlcN-GQDs were investigated. The GQDs sizes were within 20–30 nm and showed less than ten layers. A pH-sensitive and sustained release behavior was also observed for the Cur loaded nanocarrier with a total release of 37% at pH 5.5 and 17% at pH 7.4 after 150 h. In vitro cellular uptake studies through fluorescence microscopy and flow cytometry exhibited stronger fluorescence for the targeted nanocarrier against MCF-7 cells compared to the non-targeted one, owing to higher cellular internalization via GlcN receptor-mediated endocytosis. Furthermore, the MTT assay results demonstrated the nontoxicity of the bare nanocarrier with the cell viability of above 94% even at concentrations as high as 50 μg·ml−1, while the Cur/GlcN-GQDs exhibited much more cytotoxicity against MCF-7 cells compared to Cur/GQDs. It is reasonable to conclude that this advanced multifunctional nano-assembly offers superior potential for breast cancer cell-targeted delivery.

Evaluation of the best pH-sensitive linker using norbornene-derived polymers

pH-responsive drug delivery systems that are bearing with acid-sensitive linkages between therapeutic molecules and polymers have been extensively explored in cancer treatment. But there is no systematic study to choose the best acid-sensitive linker in literature. In this report, three polymer-drug conjugates were synthesized with different pH-sensitive linkers such as ester, amide, and hydrazone with the anticancer drug doxorubicin with the same polymer backbone and the same molecular weights. We believe that this study will provide useful decision-making information to choose the best linker for the stimuli-responsive delivery system. First, we synthesized three different norbornene monomers with ester linker (mono 1), amide linker (mono 2), and hydrazone linker (mono 3). Next, the homopolymerization of mono 1 (HP-DOXE), mono 2 (HP-DOXA), and mono 3 (HP-DOXH) were carried out to obtain same molecular weight of homopolymers by using second generation Grubbs’ catalyst. In vitro drug release profile indicated the importance of having the hydrazone linker that helps the drug at the mildly acidic conditions resembling the pH of the cancerous cells, compared to amide and ester linkers with the same polymer backbone and the same molecular weights of polymers. The cell viability experiments in cancerous cell lines demonstrate that the hydrazone linker kills more cells compared to ester and amide linkers up to 500 µg/mL concentration.

Three core-shell polymersomes for targeted doxorubicin delivery: Sustained and acidic release

The novel core-shell polymersomes with sustained and pH-responsive drug delivery properties is developed in this work. Doxorubicin hydrochloride (DOX) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles were prepared as a core, and then modified with polymer shells through electrostatic assembly. Three polymers, amino-terminated poly (ethylene glycol)-folate (NH2-PEG-FA), poly (allylamine hydrochloride) (PAH) and quaternary chitosan (QCS) were selected for constructing the shell layer. The successful modifications of polymer shell on the spherical DOX@PLGA core were characterized by SEM, TEM, particle size and zeta-potential. It was verified that DOX was well dispersed in core of polymersomes. In vitro drug release studies showed that DOX@PLGA core performed well in acidic pH triggered drug release. The core-shell polymersomes, especially for DOX@PLGA@PEG-FA, can be used to form pH-sensitive systems for smart and sustained drug release. FA, as the targeting agent, was exposed onto the polymersomes surface, possible for interacting with folate receptors on many cancer cells membranes. Fitted experimental data with various kinetic models, the drug release mainly follows the Fickian diffusion mechanism in the polymer system, and the erosion mechanism only existed at acidic pH. All the presented results make the proposed polymersomes a promising system for controlled and selected drug delivery.

Construction of a pH-responsive drug delivery platform based on the hybrid of mesoporous silica and chitosan

Mesoporous silica nanoparticles (MSN) have been widely used for drug delivery due to their large specific surface area and excellent biocompatibility. However, the mesoporous structure of MSN would lead to the inevitable “premature release” of the drugs, and therefore the modification of MSN for controlled delivery seems to be a necessary step. Herein, chitosan (CS) was used for the surface functionalization of MSN via amidation reaction, and the introduced CS could function as a “gatekeeper” and the drug of methotrexate (MTX) might be encapsulated in the mesopores of MSN. As a result, the “premature release” of the encapsulated MTX could be effectively circumvented with the aid of the CS cap. More importantly, the drug delivery from the hybrid of MSN and CS (MSN/CS) can be endowed with pH-sensitivity by the introduction of CS because the amide bonding between CS and MSN is highly pH-sensitive. The cumulative release of MTX from the MSN/CS is more pronounced at pH 5.0 (80.86%) than those at pH 6.8 (40.46%) and pH 7.4 (18.25%).

Nano-MOFs as targeted drug delivery agents to combat antibiotic-resistant bacterial infections.

The drug resistance of bacteria is a significant threat to human civilization while the action of antibiotics against drug-resistant bacteria is severely limited owing to the hydrophobic nature of drug molecules, which unquestionably inhibit its permanency for clinical applications. The antibacterial action of nanomaterials offers major modalities to combat drug resistance of bacteria. The current work reports the use of nano–metal-organic frameworks encapsulating drug molecules to enhance its antibacterial activity against model drug-resistant bacteria and biofilm of the bacteria. We have attached rifampicin (RF), a well-documented antituberculosis drug with tremendous pharmacological significance, into the pore surface of zeolitic imidazolate framework 8 (ZIF8) by a simple synthetic procedure. The synthesized ZIF8 has been characterized using the X-ray diffraction (XRD) method before and after drug encapsulation. The electron microscopic strategies such as scanning electron microscope and transmission electron microscope methods were performed to characterize the binding between ZIF8 and RF. We have also performed picosecond-resolved fluorescence spectroscopy to validate the formation of the ZIF8-RF nanohybrids (NHs). The drug release profile experiment demonstrates that ZIF8-RF depicts pH-responsive drug delivery and is ideal for targeting bacterial disease corresponding to its inherent acidic nature. Most remarkably, ZIF8-RF gives enhanced antibacterial activity against methicillin-resistant Staphylococcus aureus bacteria and also prompts entire damage of structurally robust bacterial biofilms. Overall, the present study depicts a detailed physical insight for manufactured antibiotic-encapsulated NHs presenting tremendous antimicrobial activity that can be beneficial for manifold practical applications.

RETRACTED: Synthesis of hollow maghemite (-Fe2O3) particles for magnetic field and pH-responsive drug delivery and lung cancer treatment

Abstract The development of smart stimuli-responsive materials for drug delivery offers new opportunities for precise drug release and cancer chemotherapy. A combination of more than one stimuli is highly desirable to further maximize the therapy by taking the advantages of various unique merits. Herein, we employed polyethylene glycol (PEG) functionalized γ-Fe2O3 particles (γ-Fe2O3/PEG) as a novel magnetic drug carrier for doxorubicin (DOX) delivery. The results showed that the γ-Fe2O3/PEG exhibited excellent thermal effects under alternating magnetic field (AMF), high magneto-thermal stability, and large DOX loading capacity. Furthermore, the effects of pH and AMF on the DOX drug release were studied. It was discovered that DOX loaded γ-Fe2O3/PEG carriers were highly responsive to both AMF and pH, resulting in significantly improved cancer cell killing capability over a single stimulus. The magnetic and pH responsive drug delivery system provided a new opportunity to minimize the side effects and maximize the therapeutic efficiency of lung cancer treatment.

Multiple Emulsions as a Biomaterial-based Delivery System for the Controlled Release of an Anti-cancer Drug

This paper focuses on developing multiple emulsions as a pH-responsive drug delivery system, for glioblastoma multiforme-GBM therapy, with reduced toxicity to healthy cells. The multiple emulsions with a stimuli-responsive biopolymer (CMC- sodium carboxymethylcellulose) were prepared in a Couette-Taylor flow contactor. As an external stimulus, the difference in pH of the cancer environment, and normal tissue, was investigated by adding salts as a triggering agent. The cancer cell lines of glioblastoma multiforme were investigated: U87MG, LN229, T98G, in order to verify emulsions’ components cytotoxicity to cells. Also normal (healthy) cells, K21-fribroblast, were analysed. Rhodamine B was used as a model drug instead of the clinically used chemotherapeutics (e.g. doxorubicin) in oncology. Results showed that multiple emulsions by themselves had no adverse effect on the viability of investigated cells, excluding one cell line: LN229. The control and modulated release rates of a model drug, by stimuli-responsive biopolymer, were established. Results confirmed the possibility of controlling the release rates of a drug in the acidic environment of the cancer cells. The proposed multiple emulsion could be explored for the potential delivery of chemotherapeutics in GBM therapy.

PH-bioresponsive poly(ε-caprolactone)-based polymersome for effective drug delivery in cancer and protein glycoxidation prevention

Artificial nanostructures using polymers to produce polymeric vesicles are inspired by the many intricate structures found in living organisms. Polymersomes are a class of self-assembled vesicles known for their great stability and application in drug delivery. They can be tuned according to their intended use by changing their components and introducing activable block copolymers that transform these polymersomes into smart nanocarriers. In this study, we propose the synthesis of a poly (ethylene oxide)-poly (ε-caprolactone)-based polymersome (PEO-PCL) loaded with GSH as a pH-responsive drug delivery molecule for cancer and protein alteration inhibition. Initially, the nanocarrier was synthesized and characterized by DLS, TEM/SEM microscopy as well as gel permeation chromatography (GPC) and 1H NMR. Their CMC formation, encapsulation efficiency, and pH responsiveness were analyzed. In addition, empty and GSH-loaded PEO-PCL polymersomes were tested for their toxicity and therapeutic effect on normal and cancer cells via an MTT test. Subsequently, protein alteration models (aggregation, glycation, and oxidation) were performed in vitro where the polymersomes were tested. Results showed that other than being non-toxic and able to highly encapsulate and release the GSH in response to acidic conditions, the nanocomposites do not hinder its content's ameliorative effects on cancer cells and protein alterations. This infers that polymeric nanocarriers can be a base for future smart biomedicine applications and theranostics.

Tumor Noninvasive and Target Embolization Therapy Platform by Intravenous Injection Based on Acidic Microenvironment-Responsive Hyperbranched Poly(amino acid)s.

Transcatheter arterial embolization (TAE) has been widely applied in treatments of unresectable or hypervascular tumors, but the procedure of TAE is complicated possibly brings inherent risks. Here, inspired by pH-responsive drug delivery systems, a new method of noninvasive and target embolization therapy by intravenous injection was developed. This method is based on a type of acidic microenvironment-responsive hyperbranched poly(amino acid) (HPTTG) to avoid using catheterization and real-time image guidance angiography, simplifying the procedure, elevating compliance and general applicability of embolization therapy. The pH value of the sol-to-gel phase transition with decreasing pH of HPTTG was controlled by adjusting the ratio of acidic amino acids in copolymers. The results of the tumor-bearing animal experiment indicate that the HPTTG have an excellent target and embolic ability; they accumulate the most at the tumor site in 8 h postinjection. Blood vessels of the tumors were occluded, and the tumors were inhibited and necrotized in about 20 days. Therefore, it is expected that HPTTG not only can be used as novel embolic materials for efficient noninvasive embolization therapy of many solid tumors but also can be used as a multifunctional platform for combined theranostics, for example, combination with controlled release, thermal ablation, multimodal imaging, synergistic therapy, etc.

PH‐responsive release of TiO 2 nanotube arrays/mesoporous silica composite based on tannic acid‐Fe(III) complex coating

In this work, TiO2 nanotube arrays/mesoporous silica composite coated with tannic acid-Fe(III) complex was prepared with a simple drip coating method. The coating significantly inhibited the burst release in the early stage of drug release. The coordination conditions of the material were different under different pH values. This resulted in different stabilities of the coating, thus controlling the release of Loxoprofen Sodium (LS) at different pH values to construct a pH-responsive drug delivery system. To demonstrate this principle, the authors loaded LS into the samples and triggered pH-induced release. The excellent biological activity of the samples was confirmed in vitro by the significant growth and differentiation of MC3T3-E1 osteoblastic cells. The data has shown that the samples had achieved intelligent control of drug release and would have a wide range of applications.

In-vitro release study through novel graphene oxide aided alginate based pH-sensitive drug carrier for gastrointestinal tract

Nanomaterials are introduced to drug carriers for enhanced drug loading, improved pH-responsive and, sustained release. Graphene oxide(GO) has gathered significant attention in biomedical applications due to its superior capacity in transporting biomolecules. Authors introduced GO with Calcium alginate(Ca-Alg) to propose a novel drug carrier for gastrointestinal tract with higher encapsulation and sustained release properties. Ciprofloxacin(CIP) has been used as a model drug. Na-Alg and GO concentration, have been optimized based on encapsulation efficiency(EE). The addition of GO improves EE from 75 % to 90 %. An in-vitro drug release study in different environments viz. aqueous, acidic(pH 2.8), and physiological pH(PBS buffer of pH 7.4) to explore the scope of pH-responsive drug delivery. The addition of GO decreases the pore size in Alg-GO, which causes a slower release of drugs in all mediums. In acidic medium, restricted delivery of 60 % drug over 100 h is observed for Alg-GO. In physiological pH, the speedy and gradual release of drugs within 3 h is observed because of the degradation of the polymeric structure.

Layered biocompatible pH-responsive antibacterial composite film based on HNT/PLGA/chitosan for controlled release of minocycline as burn wound dressing

In the present study, a promising pH-responsive wound dressing was prepared. Halloysite nanotube (HNT) composites were modified with different concentration of both poly (lactic-co-glycolic acid) (PLGA) and chitosan (CS) through the Layer-by-Layer (LbL) strategy for targeted and controlled drug delivery of minocycline (MC). The resulting composites were characterized by FT-IR, XRD, zeta-potential, TGA, FE-SEM and TEM studies. Studying the biodegradability, water uptake, photostability, and water vapor transmission of resulting composites revealed that the composite film absorbed wound secretions, did not degrade, and penetrated properly to wound during the treatment. The results of protein adsorption showed that the optimized composite (C40P60MNT) was blood-compatible. Studying the release profile of the drug showed pH-responsive behavior that was fitted with Korsmeyer-Peppas kinetic model. In-vitro antibacterial testing showed that the C40P60MNT sample had an acceptable effect on the inhibition of gram-positive and gram-negative bacteria. In wound healing test (in-vivo studies), this MC loaded composite film showed faster healing of the burn wound in rat compare to the control sample. Due to the characteristics of the optimized sample, it can be considered as a promising candidate for pH-responsive drug delivery in the treatment of chronic burn wounds.