pH-responsive Delivery System Research Articles

The fabrication of gastrointestinal pH-responsive sodium alginate surface-modified protein vehicles to improve limonin digestive stability, bioaccessibility and trans-intestinal mucus barrier capacity

Protein-based delivery systems tend to degrade too quickly in the gastrointestinal tract. Applying polysaccharide-based surface coatings on protein carriers is an effective strategy to prevent interference from gastric acid and proteases during the digestive process. This study prepared gastrointestinal pH-responsive bovine serum albumin (BSA)-myristic acid (MA) carriers using sodium alginate (SA)-based surface coating technology to improve the digestive properties and intestinal mucus penetration of limonin (LM). The results showed that ultrasonication caused uniform hydrophilic BSA and MA particle formation in optimal conditions. Fourier-transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) observations confirmed that SA adhered to the BSA-MA particle surfaces via electrostatic interaction at pH 4, causing the controlled gastrointestinal release of the self-assembled BSA-MA complexes. The subsequent SA-BSA-MA complexes displayed an LM encapsulation yield (EY) of >84%. In vitro, simulated gastrointestinal digestion indicated that compared with free LM, the SA-BSA-MA particles significantly increased the intestinal LM retention rate, bioaccessibility, and micellization rate by 45.49%, 155.48%, and 102.14%, respectively. The results of the artificial intestinal mucus experiments demonstrated that the trans-intestinal mucus barrier capacity of SA-BSA-MA particle-loaded LM was significantly enhanced. Its apparent permeability coefficient (Papp) (6.53 × 10−6 cm/s for free LM) and intestinal mucus permeability (17.56% for free LM) increased substantially to 14.22 × 10−6 cm/s and 38.22%. This study presents a gastrointestinal pH-responsive delivery system that effectively improves the ability of hydrophobic nutrients to cross the intestinal mucus barrier.

Polysuccinimide-based nanoparticle: A nanocarrier with drug release delay and zero burst release properties for effective theranostics of cancer

We have developed a novel pH-responsive delivery system consisting of oleylamine-modified polysuccinimide (PSI) nanoparticles (NPs) whereby NPs remained stable and started to release bioactive agents after 8.5 h with maximal release acquired after 36 h under physiological pH. Our NPs did not exhibit any burst release of drug, which is a key advantage in anti-cancer targeted drug delivery system. Here, the NPs function as a carrier for bioactive agents such as Curcumin and IR-780 dye whereby the former exerts its intrinsic anti-cancer abilities, the latter confers photothermal treatment application and bimodal imaging ability using photoacoustic and fluorescence imaging. In vitro and in vivo results establish that administration of folate receptors targeting PSI-NPs in U87MG model effected in a substantial decrease in tumour and photothermal laser exposure at 808 nm further ablated tumours to an almost total eradication. Our dual loaded targeted NPs demonstrated selectivity through enhanced accumulation and retention in tumours as indicated by multi-spectral optoacoustic tomography (MSOT) and fluorescence imaging (FI). Loading of Curcumin and IR-780 into PSI-NPs improved its bioavailability, allowing Curcumin to be administered into the circulation system and retention in tumours which led to the simultaneous application for a successful targeted, synergistic photothermal treatment and bimodal imaging using MSOT and FI.

Efficient delivery of methotrexate to MDA-MB-231 breast cancer cells by a pH-responsive ZnO nanocarrier

Methotrexate (MTX), an efficient chemotherapy medication is used in treating various malignancies. However, the breast cancer cell line MDA-MB-231 has developed resistance to it due to low levels of the MTX transport protein, and reduced folate carrier (RFC), making it less effective against these cancer cells. Here we designed a very simple, biocompatible, and non-toxic amine-capped ZnO quantum dots to overcome the MTX resistance on the MDA-MB-231 breast cancer cell line. The QD was characterized by HRTEM, DLS EDX, FT-IR, UV–Vis, and Fluorescence spectroscopy. MTX loading onto the QD was confirmed through fluorescence and UV–Vis spectroscopy. Additionally, extensive confocal microscopic investigations were carried out to determine whether the MTX was successfully released on the MDA-MB-231 cell line. It was discovered that QD is a better pH-responsive delivery system than the previous ones because it successfully delivers MTX to the MDA-MB-231 at a higher rate on an acidic pH than it does at a physiological pH. QD also has anticancer activity and can eradicate cancer cells on its own. These factors make the QD to be an effective pH-responsive delivery system that can improve the efficacy of the medication in therapeutic diagnosis.

Synthesis and evaluation of folate-mediated targeting and poly (β-amino ester)-mediated pH-responsive delivery system of riccardin D based on the O-carboxymethylated chitosan micelles

This study aimed to combine the active targeting function of folate (FA) receptor-mediated endocytosis with the pH-responsive drug delivery of poly (ethylene glycol)-grafted-poly (−amino ester) copolymers (PEG-PAE) in cancer targeting therapy. Herein, O-carboxymethylated chitosan (OCMC) was grafted with hydrophobic deoxycholic acid (DOCA). Further, PEG-PAE and FA-conjugated DOCA modified OCMC were synthesized to develop the potential cancer-targeted carrier (PEG-PAE-DOMC-FA), for which the structure was investigated by 1H NMR and FTIR. Then riccardin D (RD) was successfully loaded for tumor-targeted drug delivery. The particle size, zeta potential, encapsulating efficiencies, and loading content profiles of PEG-PAE-DOMC-FA/RD showed a strong dependence on the environmental pH values. The cumulative release of PEG-PAE-DOMC-FA/RD at pH 5.0 (90.63 %) was higher than pH 7.4 (51.12 %), which also indicated the pH sensitivity. Moreover, a lower IC50 and higher coumarin-6 uptake were found because of the folate-receptor-mediated endocytosis. In pharmacokinetic study, PEG-PAE-DOMC-FA/RD significantly improved the mean retention time (MRT) and AUC(0-∞) from 7.89 h and 36.1 mg/L·h of control group to 10.03 h and 123.8 mg/L·h. In the xenograft mice model, stronger antitumor efficacy and lower toxicity were confirmed. In conclusion, the multi-functional micelles could be considered as a promising vehicle for delivering hydrophobic drugs to tumors.

PH-Responsive Biomaterials for the Treatment of Dental Caries-A Focussed and Critical Review.

Dental caries is a common and costly multifactorial biofilm disease caused by cariogenic bacteria that ferment carbohydrates to lactic acid, demineralizing the inorganic component of teeth. Therefore, low pH (pH 4.5) is a characteristic signal of the localised carious environment, compared to a healthy oral pH range (6.8 to 7.4). The development of pH-responsive delivery systems that release antibacterial agents in response to low pH has gained attention as a targeted therapy for dental caries. Release is triggered by high levels of acidogenic species and their reduction may select for the establishment of health-associated biofilm communities. Moreover, drug efficacy can be amplified by the modification of the delivery system to target adhesion to the plaque biofilm to extend the retention time of antimicrobial agents in the oral cavity. In this review, recent developments of different pH-responsive nanocarriers and their biofilm targeting mechanisms are discussed. This review critically discusses the current state of the art and innovations in the development and use of smart delivery materials for dental caries treatment. The authors' views for the future of the field are also presented.

PH/Hyal-Responsive Surface-Charge Switchable Electrostatic Complexation for Efficient Elimination of MRSA Infection.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a great threat to human health worldwide, making new effective antibacterial strategies urgently desired. In this study, a cationic pH-responsive delivery system (pHSM) was developed based on poly(β-amino esters)-methoxy poly(ethylene glycol), by which linezolid (LZD) could be encapsulated to form pHSM/LZD. The biocompatibility and stability of pHSM/LZD were further enhanced by adding low-molecular-weight hyaluronic acid (LWT HA) on the surface through electrostatic interaction to form pHSM/LZD@HA, of which the positive surface charges were neutralized by LWT HA under physiological conditions. LWT HA can be degraded by hyaluronidase (Hyal) after arriving at the infection site. In vitro, pHSM/LZD@HA could rapidly change to being positively charged on the surface within 0.5 h under acidic conditions, especially when Hyal was present, thus promoting bacterial binding and biofilm penetration of pHSM/LZD@HA. In addition, the pH/Hyal-dependent accelerated drug release behavior was also observed and it is beneficial for the comprehensive treatment of MRSA infection in vitro and in vivo. Our study provides a novel strategy to develop a pH/Hyal-responsive drug delivery system for the treatment of MRSA infection.

Carboxymethyl cellulose/starch/reduced graphene oxide composite as a pH-sensitive nanocarrier for curcumin drug delivery

Nanocomposites are promising drug carriers to treat terminal cancers with few adverse effects. Herein, nanocomposite hydrogels composed of carboxymethyl cellulose (CMC)/starch/reduced graphene oxide (RGO) were synthesized via a green chemistry approach and then encapsulated in double nanoemulsions to act as pH-responsive delivery systems for curcumin, a potential antitumor drug. A water/oil/water nanoemulsion containing bitter almond oil served as a membrane surrounding the nanocarrier to control drug release. DLS and zeta potential measurements were used to estimate the size and confirm the stability of curcumin-loaded nanocarriers. The intermolecular interactions, crystalline structure and morphology of the nanocarriers were analyzed through FTIR spectroscopy, XRD and FESEM, respectively. The drug loading and entrapment efficiencies were significantly improved compared to previously reported curcumin delivery systems. In vitro release experiments demonstrated the pH-responsiveness of the nanocarriers and the faster curcumin release at a lower pH. The MTT assay revealed the increased toxicity of the nanocomposites against MCF-7 cancer cells compared to CMC, CMC/RGO or free curcumin. Apoptosis was detected in MCF-7 cells via flow cytometry tests. The results obtained herein support that the developed nanocarriers are stable, uniform and effective delivery systems for a sustained and pH-sensitive curcumin release.

Ginsenoside Rg3 Reduces the Toxicity of Graphene Oxide Used for pH-Responsive Delivery of Doxorubicin to Liver and Breast Cancer Cells.

Doxorubicin (DOX) is extensively used in chemotherapy, but it has serious side effects and is inefficient against some cancers, e.g., hepatocarcinoma. To ameliorate the delivery of DOX and reduce its side effects, we designed a pH-responsive delivery system based on graphene oxide (GO) that is capable of a targeted drug release in the acidic tumor microenvironment. GO itself disrupted glutathione biosynthesis and induced reactive oxygen species (ROS) accumulation in human cells. It induced IL17-directed JAK-STAT signaling and VEGF gene expression, leading to increased cell proliferation as an unwanted effect. To counter this, GO was conjugated with the antioxidant, ginsenoside Rg3, prior to loading with DOX. The conjugation of Rg3 to GO significantly reduced the toxicity of the GO carrier by abolishing ROS production. Furthermore, treatment of cells with GO-Rg3 did not induce IL17-directed JAK-STAT signaling and VEGF gene expression-nor cell proliferation-suggesting GO-Rg3 as a promising drug carrier. The anticancer activity of GO-Rg3-DOX conjugates was investigated against Huh7 hepatocarcinoma and MDA-MB-231 breast cancer cells. GO-Rg3-DOX conjugates significantly reduced cancer cell viability, primarily via downregulation of transcription regulatory genes and upregulation of apoptosis genes. GO-Rg3 is an effective, biocompatible, and pH responsive DOX carrier with potential to improve chemotherapy-at least against liver and breast cancers.

Diruthenium complexes as pH-responsive delivery systems: a quantitative assessment

The study of the release of carboxylate ligands from diruthenium compounds is crucial for designing drug delivery systems based on such complexes. The influence of different key parameters on the release process was evaluated throughin vivoassays.

Hollow mesoporous structured MnFe2O4 nanospheres: A biocompatible drug delivery system with pH-responsive release for potential application in cancer treatment

In this paper, a novel pH-responsive drug delivery system based on hierarchical hollow mesoporous MnFe2O4 nanospheres was developed for potential application in cancer treatment. The well-defined hollow mesoporous MnFe2O4 nanospheres were directly fabricated via a facile one-step solvothermal approach without the involvement of additional templates. A mechanism of inside-out Ostwald ripening was suggested to account for the formation of hollow mesoporous nanostructures. The morphology, crystal structure, chemical composition, magnetic properties, thermal stability and mesoporous characteristics of the fabricated MnFe2O4 nanospheres were comprehensively assessed based on various analysis techniques. The resulting hollow mesoporous MnFe2O4 nanospheres with a high biocompatibility were able to be served as a nanocarrier for loading and delivering of anticancer drug doxorubicin (DOX). In vitro drug release study revealed that DOX release from DOX-loaded MnFe2O4 nanospheres was significantly restrained in pH 7.4 phosphate buffer solution (PBS), while it was markedly accelerated in pH 4.5 PBS. The results of cytotoxicity assay and inverted biological microscopy demonstrated that the DOX-loaded MnFe2O4 nanospheres were more cytotoxic against HepG2 cells than MnFe2O4 nanospheres due to the evident inhibition effect of released DOX from the constructed drug delivery system. Therefore, the developed pH-responsive delivery system will have a great potential for its practical application in cancer treatment.

Facile synthesis of curcumin-containing poly(amidoamine) dendrimers as pH-responsive delivery system for osteoporosis treatment

Osteoporosis is an age-related metabolic disease of bone, resulting in bone pain and even bone fragility and brittle fracture. Inhibiting overactive osteoclasts while promoting osteoblast activity is an ideal way to treat osteoporosis. Previous studies have demonstrated that natural compounds, such as curcumin (Cur) have dual roles both in promoting bone formation and inhibiting bone resorption, making them promising candidates for osteoporosis treatment. However, their poor water solubility, high dosage of curative effect and significant toxicity to other organs have largely limited their clinical translations. In this study, a novel method was reported to conjugate Cur and poly(amidoamine) dendrimers (PAD) using hexachlorocyclotriphosphazene (HCCP) as the linkage through a one-pot reaction, forming stable and uniform Cur loaded nanospheres (HCCP-Cur-PAD, HCP NPs). Owing to the hydrophilicity of PAD and hydrophobicity of Cur, HCP NPs can self-assemble into nanoparticles with particle size of 138.8 ± 78.7 nm and display excellent water dispersity. The loading capacity of Cur can reach 27.2% and it can be released from HCP NPs with pH-responsiveness. In vitro experimental results demonstrated that the HCP NPs entered lysosomes by endocytosis and proved dual anti-osteoporosis effects of inhibiting osteoclasts and promoting osteoblasts.

Novel pH-responsive and mucoadhesive chitosan-based nanoparticles for oral delivery of low molecular weight heparin with enhanced bioavailability and anticoagulant effect

Low molecular weight heparin (LMWH) shows great anticoagulant effect for prevention and treatment of deep venous thrombosis. However, its oral administration is seriously hindered by multiple obstacles. In this study, a pH-responsive delivery system was developed to protect LMWH from gastrointestinal tract degradation and facilitate its absorption across gastrointestinal mucosa. The LMWH-loaded nanoparticles (pH-TCS/O-CMCS@LMWH) were prepared by ionic-crosslinking reaction between positive-charged amino groups of thiolated chitosan (TCS) as well as o-carboxymethyl chitosan (O-CMCS) and oppositely charged HP55. As a result, the prepared nanoparticles proved to spherical shape with an average size of 332 nm, high encapsulation efficiency of 96.6% and drug-loading content of 12.04 IU/mg. The proposed pH-TCS/O-CMCS@LMWH also showed good colloidal stability, potential mucoadhesive effect and desirable pH-responsive drug release behavior, which decreased pre-mature LMWH release in acidic environment but increase its targeted release in intestine environment. After oral administration, the pH-TCS/O-CMCS@LMWH shown enhanced bioavailability and significant antithrombotic effect in a rat model of venous thrombosis. In conclusion, pH-TCS/O-CMCS nanoparticles can be successfully hold great promising for oral administration of LMWH and potential treatment for thrombosis.

Receptor-Targeted Dual pH-Triggered Intracellular Protein Transfer.

Protein therapeutics are of widespread interest due to their successful performance in the current pharmaceutical and medical fields, even though their broad applications have been hindered by the lack of an efficient intracellular delivery approach. Herein, we fabricated an active-targeted dual pH-responsive delivery system with favorable tumor cell entry augmented by extracellular pH-triggered charge reversal and tumor receptor targeting and pH-controlled endosomal release in a traceless fashion. As a traceable model protein, the enhanced green fluorescent protein (eGFP) bearing a nuclear localization signal was covalently coupled with a pH-labile traceless azidomethyl-methylmaleic anhydride (AzMMMan) linker followed by functionalization with different molar equivalents of two dibenzocyclooctyne-octa-arginine-cysteine (DBCO-R8C)-modified moieties: polyethylene glycol (PEG)-GE11 peptide for epidermal growth factor receptor-mediated targeting and melittin for endosomal escape. The cationic melittin domain was masked with tetrahydrophthalic anhydride revertible at mild acidic pH 6.5. At the optimally balanced ratio of functional units, the on-demand charge conversion at tumoral extracellular pH 6.5 in combination with GE11-mediated targeting triggered enhanced electrostatic cellular attraction by the R8C cell-penetrating peptides and melittin, as demonstrated by strongly enhanced cellular uptake. Successful endosomal release followed by nuclear localization of the eGFP cargo was obtained by taking advantage of melittin-mediated endosomal escape and rapid traceless release from the AzMMMan linker. The effectiveness of this multifunctional bioresponsive system suggests a promising strategy for delivery of protein drugs toward intracellular targets. A possible therapeutic relevance was indicated by an example of cytosolic delivery of cytochrome c initiating the apoptosis pathway to kill cancer cells.

Advances in pH-responsive drug delivery systems

Bioresponsive nanosystems are increasingly important in a wide range of applications such as drug delivery, tissue engineering, imaging diagnostics and biosensors. Among these, pH-responsive delivery systems have gained considerable attention because of their ability in response to disease microenvironment and pH-triggered release of therapeutic drugs for therapy. In view of the importance of pH-sensitive nano-delivery systems, this review article highlights four types of pH-responsive modes, the corresponding design strategies, applications and future directions by smart design of pH-sensitive nanosystems for precision imaging or therapy.

Metal-phenolic coated and prochloraz-loaded calcium carbonate carriers with pH responsiveness for environmentally-safe fungicide delivery

• A porous CaCO 3 carrier coated metal-polyphenol films was prepared for fungicide delivery. • Prochloraz-loaded carrier (PC@TA/Cu) exhibited tailored pH-responsive properties. • PC@TA/Cu provided sustained protection in oilseed rape against Sclerotinia disease. • Metal-polyphenol coating could improve deposition efficiency toward oilseed rape leaves. The study of release mechanisms of pesticides with respect to environmental and biological factors facilitates improvement in pesticide use efficiencies and reduction in environmental risk. In this study, prochloraz (Pro), a highly effective fungicide, was loaded into starch-doped porous calcium carbonate (CaCO 3 ), which was subsequently coated with a metal–phenolic film to prepare a pH-responsive delivery system (PC@TA/Cu). Results demonstrated that CaCO 3 had a mean diameter of 1.55 µm and its loading capacity for Pro was ~15.2%. PC@TA/Cu microparticles show good adhesion to rapeseed oil leaves and resisted washout with simulated rainwater. The cumulative release rate of PC@TA/Cu particles at pH = 3 was 1.63 times higher than that in near-neutral pH environment for 48 h. This pH-responsive release characteristic could be associated with the oxalic acid secreted by Sclerotinia sclerotiorum . The control effect against Sclerotinia disease with 100 μg/mL of Pro content of PC@TA/Cu was 56.8% after 7 d, while that of Pro EW (emulsion in water) was 45.8%. Finally, biosafety tests showed a 4-fold reduction in the acute toxicity of PC@TA/Cu to zebrafish, compared to the that of Pro technical. The carrier (CaCO 3 @TA/Cu) had no significant effect on the growth of rapeseed oil seedlings. The results showed that the prepared PC@TA/Cu has long-lasting disease control capability and significantly reduced toxicity to non-target organisms, making it valuable for potential applications.

In situ vaccination and gene-mediated PD-L1 blockade for enhanced tumor immunotherapy

Despite of the promising achievements of immune checkpoints blockade therapy (ICB) in the clinic, which was often limited by low objective responses and severe side effects. Herein, we explored a synergistic strategy to combine in situ vaccination and gene-mediated anti-PD therapy, which was generated by unmethylated cytosine-phosphate-guanine (CpG) and pshPD-L1 gene co-delivery. PEI worked as the delivery carrier to co-deliver the CpG and pshPD-L1 genes, the formed PDC (PEI/DNA/CpG) nanoparticles were further shielded by aldehyde modified polyethylene glycol (OHC-PEG-CHO) via pH responsive Schiff base reaction for OHC-PEG-CHO-PEI/DNA/CpG nanoparticles (P(PDC) NPs) preparation. All steps could be finished within 30 min. Such simple nanoparticles achieved the synergistic antitumor efficacy in B16F10 tumor-bearing mice, and the amplified T cell responses, together with enhanced NK cells infiltration were observed after the combined treatments. In addition, the pH responsive delivery system reduced the side effects triggered by anti-PD therapy. The facile and effective combination strategy we presented here might provide a novel treatment for tumor inhibition.

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.

Thermal protection and pH-gated release of folic acid in microparticles and nanoparticles for food fortification.

Encapsulation provides efficient approaches to increase stability and delivery of poorly soluble bioactive components, predominantly for fortification of beverages and similar liquid-based foods. In this study, folic acid was encapsulated within conventional and emulsion-templated alginate-pectin hydrogels, proliposomes, and a combination thereof. The stability of these systems was examined under various environmental conditions (pH 1.2-9.0, 25-85 °C, dark/light). The techniques demonstrated efficient and relatively straightforward production of well-defined microparticles and nanoparticles (350 nm to 250 μm). Dispersed folic acid provided a delivery system with unique pH-responsive features, which offered prolonged stability during food storage, and indicated increased release at the site of absorption upon ingestion. This formulation had no limitation due to particle size, while at the same time it allowed high encapsulation efficiencies (80%-100%), as compared to the low encapsulation efficiency achieved by solubilisation (6%). At the low pH that is expected in the stomach, leaching of the dispersed folic acid was prevented, while at the pH that is expected in the intestine, there was complete release via solubilisation and carrier swelling. Overall, the optimum for food processing and storage was pH 3.0, where ≥70% of 50% to 200% of the recommended daily allowance of folic acid remained in the alginate-pectin beads after 6 months at room temperature in the dark. The thermal properties were enhanced by emulsion-templated alginate-pectin beads and proliposomes. In this way, 30% to 75% retention of folic acid was achieved at temperatures ≤90 °C, where the proliposomes reinforced within a polysaccharide network achieved the highest level of protection.

Injectable Biocompatible Hydrogels from Cellulose Nanocrystals for Locally Targeted Sustained Drug Release.

Injectable hydrogels from biocompatible materials are in demand for tissue engineering and drug delivery systems. Here, we produce hydrogels from mere cellulose nanocrystals (CNCs) by salt-induced charge screening. The injectability of CNC hydrogels was assessed by a combination of shear and capillary rheology, revealing that CNC hydrogels are conveyed via plug flow in capillaries allowing injection with minimal impact on mechanical properties. The potential of CNC hydrogels as drug carriers was elaborated by the in vitro release of the model protein bovine serum albumin (BSA), poorly water soluble tetracycline (TC), and readily soluble doxorubicin (DOX) into physiological saline and simulated gastric juice. For TC, a burst release was observed within 2 days, whereas BSA and DOX both showed a sustained release for 2 weeks. Only DOX was released fully from the hydrogels. The different release patterns were attributed to drug size, solubility, and specific drug-CNC interactions. The biocompatibility of CNC hydrogels and maintained bioactivity of released DOX were confirmed in a HeLa cell assay. The drug release was modulated by the incorporation of sucrose or xanthan gum in CNC hydrogels, whereas altering CNC concentration showed minor effects. The release into simulated gastric juice at pH 2 ceased for BSA due to charge inversion and electrostatic complexation, but not for smaller TC. Thus, CNC hydrogels may act as pH-responsive delivery systems that preserve drugs under gastric conditions followed by pH-triggered release in the duodenum.

Tunable Hollow Bimetallic MnFe Prussian Blue Analogue as the Targeted pH-Responsive Delivery System for Anticancer Drugs.

Owning to the improved ability of selectivity and penetration toward cancer cells, drug delivery systems (DDSs) play essential roles in chemotherapy for solid tumors. Herein, a series of bimetallic MnFe Prussian blue analogues (PBAs) with a tunable nanostructure was prepared by using sodium citrate (SC) as a structure regulator (represented by MnFe-PBA-SC). An advanced targeted drug delivery system was obtained by adding folic acid (FA) to the preparation system of MnFe-PBA-SC nanospheres (denoted as MnFe-PBA-SC-FA). The shape of pure MnFe PBA was changed from a typical nanocube to a hollow nanosphere when adding SC, leading to the formation of the core-shell nanospheres of the MnFe-PBA-SC-FA composite. The hollow nanostructures and intrinsic cavities in PBA can carry large amounts of doxorubicin (DOX), showing a high loading efficiency of MnFe-PBA-SC1.0-FA (91.8%), which was higher than that in MnFe-PBA-SC0.5 (63.2%). Additionally, the series of MnFe-PBAs showed pH-responsive drug release behaviors. A cell viability assay illustrated no remarkable cytotoxicity of MnFe-PBA-SC-FA against human breast cancer cells, Michigan Cancer Foundation-7 (MCF-7) cells, for 24 h. Confocal laser scanning showed that the MnFe-PBA-SC1.0-FA/DOX system significantly entered FA receptor-expressing MCF-7 cells in vitro and in vivo, while an increased DOX release was observed in the cytoplasm of the MCF-7 cells. In consequence, this novel anticancer delivery system based on bimetallic PBAs can be potentially applied to drug delivery.