pH-responsive Drug Release Research Articles

PH and Thermoresponsive PNIPAm-co-Polyacrylamide Hydrogel for Dual Stimuli-Responsive Controlled Drug Delivery.

The therapeutic delivery system with dual stimuli-responsiveness has attracted attention for drug delivery to target sites. In this study, we used free radical polymerization to develop a temperature and pH-responsive poly(N-isopropyl acrylamide)-co-poly(acrylamide) (PNIPAM-co-PAAm). PNIPAm-co-PAAm copolymer by reacting with N-isopropyl acrylamide (NIPAm) and acrylamide (Am) monomers. In addition, the synthesized melamine-glutaraldehyde (Mela-Glu) precursor was used as a cross-linker in the production of the melamine cross-linked PNIPAm-co-PAAm copolymer hydrogel (PNIPAm-co-PAAm-Mela HG) system. The temperature-responsive phase transition characteristics of the resulting PNIPAM-co-PAAm-Mela HG systems were determined. Furthermore, the pH-responsive drug release efficiency of curcumin was investigated under various pH and temperature circumstances. Under the combined pH and temperature stimuli (pH 5.0/45 °C), the PNIPAm-co-PAAm-Mela HG demonstrated substantial drug loading (74%), and nearly complete release of the loaded drug was accomplished in 8 h. Furthermore, the cytocompatibility of the PNIPAm-co-PAAm-Mela HG was evaluated on a human liver cancer cell line (HepG2), and the findings demonstrated that the prepared PNIPAm-co-PAAm-Mela HG is biocompatible. As a result, the PNIPAm-co-PAAm-Mela HG system might be used for both pH and temperature-stimuli-responsive drug delivery.

Self-assembly of DNA nanospheres with controllable size and self-degradable property for enhanced antitumor chemotherapy

Controllable size, self-degradability and targeting property are important for a precise improvement of anticancer effects and reduction of side effects of drug vehicles. Here, a series of DNA nanospheres with controllable size and self-degradation ability were constructed through the hybridization of two i-motif strands and two linker strands for targeted cancer therapy. DNA nanospheres with different sizes were fabricated by regulating the linker sequence, and their pH-responsive self-degradation property was realized by the introduction of the i-motif strand. Moreover, the ZY11 aptamer was introduced to endow the DNA nanospheres with targeting property toward SMMC-7721 cancer cells. The results revealed that the appropriate size of DNA nanospheres (80 nm) highly promoted the internalization by mammalian cells. The results of DLS, AFM and CD spectra showed that the DNA nanospheres were stable in a physiological environment but they self-degraded in a slightly acidic environment due to the existence of the i-motif strand. Moreover, the fluorescence of DOX@AP-NSs2 was triple at pH = 5.0 than at pH = 7.4, which further confirmed the pH-responsive drug release performance. The above results proved that the use of DOX@AP-NSs2 is a promising approach to accelerate the rapid release of drugs into the tumors and avoid drug leakage into the normal tissue. The results at a cellular level and in vivo confirmed the pH-responsive targeted antitumor effect. Hence, the novel DNA nanospheres with controllable size and self-degradable property represent a potential tool for targeted drug delivery and cancer therapy.

Hypoxia-alleviating hemoglobin nanoclusters for sensitizing chemo-photodynamic therapy of cervical cancer

Hypoxia-alleviating hemoglobin (Hb) nanoclusters (NCs) have been developed for sensitizing combined chemo-photodynamic therapy (chemo-PDT) of cervical cancer. Hb was conjugated with chlorin e6 and biotinylated polyethylene glycol and adsorbed with doxorubicin (DOX), resulting in the self-assembly of 220 nm diameter protein NCs. These oxygen-carrying NCs, namely DOX@HPBC, exhibited improved colloidal stability in the serum compared to that of native Hb and pH-responsive drug release favorable for cancer treatment. DOX@HPBC alleviated hypoxia by 64.8% in HeLa cells cultured under hypoxia and normalized the levels of related biomarkers, HIF-1α and MDR1, with enhanced cellular uptake via biotin–receptor interactions. Moreover, antitumor efficacy tests performed in HeLa monolayer and spheroid cultures revealed that DOX@HPBC possessed 3.8-fold improved therapeutic efficacy compared to DOX and chlorin e6 physical mixture, showing synergism between chemotherapy and PDT. DOX@HPBC-mediated chemo-PDT significantly suppressed tumor growth in heterotopic (96.6% reduction in tumor volume compared to no-intervention) and orthotopic (comparable uterus weight to the normal group) HeLa-xenografted mice with no significant toxicity. These results showed the hypoxia amelioration effect, which lowered HIF-1α and MDR1 levels in tumor tissues, and efficient DOX distribution to hypoxic regions of the tumor, suggesting that DOX@HPBC could be a promising chemo-PDT strategy for cervical cancer treatment.

Fabrication of baicalein-encapsulated zeolitic imidazole framework as a novel nanocomposited wound closure material to persuade pH-responsive healing efficacy in post-caesarean section wound care.

Baicalein is a plant-derived compound, it has widespread attention among biomedical researchers due to its biocompatibility and efficient biological activities. But it has non-solubility in physiological conditions and short bioavailability in the clinical process. The Discovery of a stimuli-based drug delivery system (DDS) is a perfect strategy to improve the bioactivity of baicalin in post-caesarean section wound care. We prepared a baicalein-encapsulated pH-responsive DDS with a zeolite imidazole framework-8 (ZIF-8) as a carrier. We investigated the material characteristics of DDS in terms of crystal structure, surface area morphology, particle size, FTIR, UV-vis, Powder XRD, and BET analysis techniques. The in vitro cytotoxicity, biocompatibility, and cell proliferation properties of BA@ZIF-8 were assessed against human fibroblast L929 cells. In vitro studies showed that BA@ZIF-8 nanocomposite significantly enhanced the biocompatibility against L929 cells after 72 h post-exposure. The pH-responsive drug release kinetics shows excellent baicalein release under acidic conditions and without unwanted drug release in physiological conditions. Wound scratch assay results revealed, that BA@ZIF-8 nanocomposite-treated cells exhibit the fastest cell proliferation and migration process in a very short period. In the antibacterial activity study, nanocomposite exposed dose depended on inhibition against wound infectious pathogens. The overall study signifies that BA@ZIF-8 nano-DDSs are effective and suitable DDS for stimuli-based post-caesarean section wound care.

ZIF-8 as a protein delivery system enhances the application of dental pulp stem cell lysate in anti-photoaging therapy

Stem cell therapy is of great therapeutical potential for anti-aging treatment. Lysates of dental pulp stem cells (DPSC) are rich in numerous cytokines, which can improve the cell growth environment and enhance collagen synthesis in the skin. Frequently, the instability of protein growth factors severely restricts their applications in living systems. In this study, a strategy for delivering the growth factors of DPSC lysate via protein-encapsulated zeolitic imidazolate framework-8 (ZIF-8) nanoparticles was developed. Using ZIF-8 as protein-encapsulated nanoparticles, a ZIF-8@DPSC lysate (ZIF-8@DL) with pH-responsive drug release was produced. ZIF-8@DL demonstrated superior cutaneous uptake, cutaneous penetration, and retention capacity in vivo compared to DPSC lysate. Moreover, ZIF-8@DL demonstrated excellent in vitro and in vivo biocompatibility. Subcutaneous microneedle injection of ZIF-8@DL into a mouse photoaging model resulted in significantly improved epidermal thickness, dermal collagen deposition, and cutaneous inflammation, with no apparent adverse effects. This study provides a safe and efficient method for enhancing the therapeutic application of DPSC lysate. It has the potential to expedite the clinical implementation of lysate-based anti-photoaging therapy.

Fabrication and properties of multi-functional polydopamine coated Cu/F-codoped hydroxyapatite hollow microspheres as drug carriers

Due to its excellent bone conductivity and drug adsorption as well as pH-responsive drug release property, hydroxyapatite (HAp) is widely used as a drug carrier in bone repair field. Here, we report for the first time a novel multi-functional polydopamine (PDA) coated Cu/F-codoped HAp (Cu/F-HAp-PDA) hollow microspheres. Both Cu2+ and F- were successfully doped into the lattice of HAp and uniformly distributed in the shell of hollow microspheres through a one-step hydrothermal synthesis. Then PDA was coated homogeneously on the outer layer of Cu/F-HAp hollow microspheres. Both Cu/F-HAp and Cu/F-HAp-PDA samples displayed high drug loading efficiency and pH responsive drug release behavior. Moreover, the obtained Cu/F-HAp-PDA hollow microspheres exhibited excellent photothermal conversion efficiency and photothermal stability. The molecular dynamics simulations showed that PDA and HAp can form mutual binding mainly through Ca-O bonding, while doxorubicin (DOX) is mainly bound to PDA molecules through hydrogen bonding and π-π stacking interaction.

Cupriavidus necator-Produced Polyhydroxybutyrate/Eudragit FS Hybrid Nanoparticles Mitigates Ulcerative Colitis via Colon-Targeted Delivery of Cyclosporine A.

Polyhydroxybutyrate (PHB) has emerged as a novel material for replacing various plastics used in the medical field. However, its application as a drug-delivery carrier for colitis-targeted delivery has not been explored. In this study, we used biosynthesized PHB combined with Eudragit FS (EFS) and cyclosporine A (CSA) to develop pH-responsive controlled CSA-releasing nanoparticles (CSA-PENPs) for colitis-targeted drug delivery and demonstrated its enhanced therapeutic efficacy in a dextran sulfate sodium (DSS)-induced murine colitis model. PHB was successfully biosynthesized in the bacterium Cupriavidus necator, as demonstrated by 1H-NMR and FT-IR analyses. CSA-PENPs were fabricated via the oil-in-water emulsion solvent evaporation method. Owing to the potent pH-responsive and sustained drug release properties provided by PHB and EFS, CSA-PENPs could deliver a sufficient amount of CSA to inflamed tissues in the distal colon; in contrast, CSA-loaded EFS nanoparticles displayed premature burst release before reaching the target site. Due to enhanced CSA delivery to colitis tissues, CSA-PENPs exhibited potent anti-inflammatory effects in the DSS-induced murine colitis model. Overall, CSA-PENPs could be a promising drug-delivery system for treating ulcerative colitis.

Synthesis of stable calcium carbonate nanoparticles for pH-responsive controlled drug release

The construction of controlled release for drugs is a promising strategy in disease treatment, which can improve the bioavailability of utilized drugs and reduce the side effects. Herein, a simple and green strategy was developed to prepare stable amorphous calcium carbonate (ACC) using polyvinyl pyrrolidone (PVP) as stabilizer. The crystallization behavior of ACC nanoparticles in methanol–water system and the effect of PVP content on ACC was investigated. Most importantly, the obtained ACC-PVP exhibited high drug loading efficiency and pH responsive release properties for anticancer drugs 5-Fluorouracil (5-FU) and curcumin (CUR) in phosphate buffer solution and simulated gastric juice. All evidences demonstrate that smart mesoporous ACC-PVP nanoparticles provide a potential clinical application platform for cancer therapy.

Mesoporous silica (SBA-15) with enriched amidoxime functionalities for pH-controlled anticancer drug delivery

Amidoxime (AMI), an amphoteric functional ligand, mesoporous silica material (SBA-15@AMI NPs) was prepared and the pH-responsive drug release behavior was examined using Dox as model anticancer drug. Further, the cytocompatibility and the cell uptake results revealed that SBA-15@AMI NPs could be applied as pH-responsive drug delivery applications in cancer therapy. • Developing pH- responsive drug delivery system is attracted a great concern. • An amphoteric ligand functionalized SBA-15@AMI NPs for pH-responsive drug delivery system has been proposed. • The SBA-15@AMI NPs is applicable for delivery of anticancer drugs in cancer therapy. Amidoxime (AMI) functionalized mesoporous silica material (SBA-15@AMI NPs) was synthesized by surface modification approaches. This method allows for the creation of a higher concentration of amidoxime ligand groups to the SBA-15's surface without affecting the morphology. The synthesized SBA-15@AMI NPs were verified using a range of instrumental characterizations. Further, the drug loading and pH-responsive release behavior of the SBA-15@AMI NPs were examined using Dox as model anticancer drug. The biocompatibility and cellular uptake behavior was studied using MCF-7 cell line. Overall, the prepared SBA-15@AMI NPs could be applied as pH-responsive drug delivery applications in cancer therapy.

Tumor microenvironment targeting and regulating iron-based metal-organic framework for magnetic resonance imaging guided synergetic therapy of doxorubicin and hydroxyl radicals

Fe3+ and 2-methylimidazole were selected to prepare tumor microenvironment targeted and regulated multifunctional drug carrier Fe-MOFs. The fact that Doxorubicin hydrochloride (DOX·HCl) release climbed 70% from 25% upon regulating the pH from 7.4 to 5.8 proved the pH responsive drug release of Fe-MOFs. Hydroxyl radicals (·OH) analysis proved that Fe-MOFs only generated hydroxyl radicals at pH 5.8, and dissolved oxygen performance showed the O2 was produced during the process, which was expected to regulate hypoxia in tumor cells to increase anticancer effect. Cell viability experiments proved the selectivity of Fe-MOFs and the excellent performance of synergy therapy of DOX·HCl and hydroxyl radicals. In vivo magnetic resonance imaging experiments demonstrated excellent performance of positive images. All experiments showed that Fe-MOFs can be used for image-guided collaborative treatment to improve treatment efficiency and reduce side effects.

A pH-responsive chiral mesoporous silica nanoparticles for delivery of doxorubicin in tumor-targeted therapy

The purpose of this study was to develop a nano-drug delivery system with intelligent stimuli-responsive drug delivery in tumor microenvironment (TME). Based on chiral mesoporous silica nanoparticles (CMSN) with a chiral recognition function in our previous research, a pH-responsive CMSN (CS-CMSN) was successfully prepared by chemical modification of chitosan (CS), and the related physicochemical properties, drug release performance, potential anti-tumor effect, and biological safety were studied. The results showed that the CS-CMSN were successfully modified by CS. Moreover, CS-CMSN displayed superior encapsulation ability for doxorubicin (DOX) and exhibited controllable pH-responsive drug release properties. In particular, in a physiological environment (pH 7.4/6.5), CS shielded the nanopores, prevented DOX release, and minimized side effects on normal cells. Once the CS-CMSN was exposed to the TME (pH 5.0), the pH-sensitive moiety of CS was cleaved in an acidic environment, along with the rapid release of DOX. In vitro cell experiments further proved that DOX@CS-CMSN was more strongly taken up by 4T1 cells and could enhance the toxicity to 4T1 tumor cells as well as promote cell apoptosis. More importantly, CS-CMSN were shown to have good biosafety in vitro and in vivo. Overall, the delivery of DOX by CS-CMSN nanocarriers is a promising strategy for tumor-targeted therapy.

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.

Folic acid-functionalized cerium oxide nanoparticles as smart nanocarrier for pH-responsive and targeted delivery of Morin in breast cancer therapy

• A novel FA-tagged CeO 2 NPs were synthesized for targeting human breast cancer cells. • The NPs were loaded with morin, a natural flavonoid to form Morin-CeO 2 -NH-FA nanohybrids. • Morin-CeO 2 -NH-FA nanohybrids exhibited pH-dependent drug release property. • Morin-CeO 2 -NH-FA nanohybrids showed significant anticancer effect both in vitro and in vivo . • Morin-CeO 2 -NH-FA nanohybrids did not exhibit any systemic toxicity. Nanoceria (CeO 2 NP) has emerged as a promising carrier for effective delivery of various anticancer drugs. Herein, folic acid (FA) conjugated and amine-functionalized CeO 2 NPs (CeO 2 -NH-FA) have been synthesized for targeted and controlled delivery of Morin (a natural flavonoid) towards folic acid overexpressed breast cancer cells. Morin was successfully loaded onto the surface of CeO 2 -NH-FA via metal ion-ligand coordination bonds to form Morin-CeO 2 -NH-FA nanohybrids. The as synthesized nanohybrid exhibited nearly spherical shape with an average diameter of ∼ 2–3 nm. Moreover, the nanohybrid displayed drug loading content of ∼ 10 % along with pH-responsive drug release behaviour. The nanohybrids exhibited significant cytotoxic effect towards human breast cancer (MCF-7) cells via the generation of intracellular reactive oxygen species (ROS) which subsequently induced mitochondria-dependent apoptotic cell death. In addition, the nanohybrids also triggered potential anti-migratory effect. The in vivo results also revealed the highest anticancer effect of the Morin-CeO 2 -NH-FA nanohybrids in tumor-bearing mice as compared with free Morin and CeO 2 -NH-FA. Furthermore, Morin-CeO 2 -NH-FA nanohybrid did not show any significant change in serum biochemical parameters. To gain possible mechanistic pathway, we carried out molecular docking study of Morin with Bcl-2 protein which revealed that Morin can bind to Bcl-2 with an affinity of −7.1 kCal/mol. The pronounced anticancer effect of the nanohybrid towards breast cancer cells is mainly ascribed to the combined cytotoxic effect of both Morin as well as nanoceria. Overall, our study represents Morin-CeO 2 -NH-FA nanohybrid as a potential drug delivery vehicle with improved therapeutic efficacy against cancer.

Multi-functional Fe3O4@HMPDA@G5-Au core-releasable satellite nano drug carriers for multimodal treatment of tumor cells

Combination therapy has become an effective strategy for tumor treatment, but the preparation of drug nanocarriers with the high requirements still lacked exploration. In this paper, hollow shell-layer mesoporous polydopamine (HMPDA) was constructed on Fe3O4 nanoparticles (the magnetic core), and small-sized G5-Au nanoparticles (AuNPs) as the releasable satellite carriers for tumor deep treatment were modified on HMPDA surface, then the nucleus-satellite Fe3O4@HMPDA@G5-Au nano drug delivery carriers were obtained. The therapy drug could be loaded in the mesoporous structure of HMPDA and G5-Au nanoparticles, so the drug loading capacity was relatively large. The Fe3O4@HMPDA@G5-Au composite nano carriers also had good photothermal properties, because polydopamine (PDA) and AuNPs were both good photothermal agents. Combination of photothermal therapy (PTT) and drug therapy could significantly enhance the ablation of tumor cells with minor side effects. In addition, the decomposition of H2O2 in the tumor site catalyzed by the AuNPs could also produce oxygen to alleviate tumor hypoxia. In addition, because of the magnetic properties of Fe3O4 nanoparticles, the Fe3O4@HMPDA@G5-Au nano drug delivery carriers also had magnetic targeting performance and could reach the specified position under the guidance of external magnetic field. The results showed that the average DOX loaded amount of the prepared carriers was 473.83 mg/g, the drug release rate in 24 h could achieve 61.3 %. The cytotoxicity test showed that the drug loaded carriers had a significant inhibitory effect on HepG2 cells. The drug-loaded core-satellite nanocarriers could play a good synergistic treatment effect on cancer under the multi effect synergy of PPT, drug therapy, magnetic targeting and pH-responsive drug release.

PH-responsive nanoprodrugs combining a Src inhibitor and chemotherapy to potentiate antitumor immunity via pyroptosis in head and neck cancer

As the prominent feature of the development and progression of head and neck squamous cell carcinoma (HNSCC) is immunosuppression, therapeutic strategies to restore antitumor immunity have shown promising prospects. The efficacy of chemotherapy, a mainstay in HNSCC treatment, is exemplified by cytotoxic effects as well as immunostimulation, whereas compensatory activation of prosurvival signals in tumor tissues may compromise its efficacy. Aberrant activation of Src is present in many human malignancies including HNSCC, and is implicated in chemotherapy resistance. In this regard, tumor-microenvironment-responsive prodrug nanomicelles (PDO NPs) are rationally designed to combine chemotherapy (oxaliplatin, OXA) and Src inhibitors (dasatinib, DAS) for HNSCC therapy. PDO NPs are constructed by chemically modifying small-molecule prodrugs (DAS-OXA) loaded in block copolymer iPDPA with pH-triggered transforming capability. PDO NPs can controllably release drugs in response to tumor acidity, thus increasing tumor accumulation and therapeutic efficacy. Moreover, PDO NPs can elicit pyroptosis of tumor cells and induce T-cell-mediated antitumor immunity in murine HNSCC models. In summary, nanoprodrugs integrating Src inhibitors enhance the immunological effects of chemotherapy and provide insight into promising approaches for augmenting immunochemotherapy for HNSCC. Statement of SignificanceIn this study, pH-responsive nanomicelles (PDO NPs) were constructed by loading a small molecular prodrug synthesized by the Src inhibitor dasatinib and the chemotherapy drug oxaliplatin into the amphiphilic block copolymer iPDPA to improve the immunological effects of chemotherapy for HNSCC. These nanomicelles can efficiently accumulate in tumor cells and achieve pH-responsive drug release. The PDO NPs can induce pyroptosis of tumor cells and potentiate antitumor immunity in subcutaneous and syngenetic orthotopic HNSCC mouse models, which may present a promising strategy to enhance immunochemotherapy for HNSCC.

Design and scale-up of amorphous drug nanoparticles production via a one-step anhydrous continuous process

Polymeric nanoparticle drug delivery systems are increasingly viewed as crucial building blocks for efficacious treatments of disease conditions. However, production methods at commercially practical scales pose a significant challenge for successfully translating such technology. This paper describes a novel, anhydrous, twin-screw extrusion (TSE) platform-based technology to overcome the issues associated with developing and scale-up production of nanoparticulate drug delivery systems. With polyol as the process medium, the proposed TSE platform enables the encapsulation of the drug and reduction of particle size in a one-step process without the requirement for organic solvents or water. pH-responsive nanoparticle drug delivery of two nonsteroidal anti-inflammatory drugs, naproxen, and celecoxib, was successfully produced using the TSE process. Remarkably, these resulted in nanoparticles with sizes ranging from 80 to 240 nm, up to 98 % drug encapsulation efficiency, and maximum production throughput of 400 g/hour. pH-responsive drug release for both naproxen and celecoxib was also achieved: immediate drug release with enhanced solubility was obtained for naproxen-Eudragit®E nanoparticles (6 times higher) at pH 1.2 and celecoxib-HPMCAS nanoparticles (15 times higher) at pH 6.8, whilst sustained drug release was achieved for naproxen-Eudragit®E nanoparticles at pH 6.8 and celecoxib-HPMCAS nanoparticles at pH 1.2. We expect this platform technology to streamline the development and scale-up production of various polymeric nanoparticle drug delivery systems.

Hierarchical hollow monetite microspheres assembled with mesoporous nanosheets: Synthesis and applications in superior adsorbents for lead ions and pH-responsive release drug carrier

Hierarchical hollow monetite microspheres assembled with mesoporous nanosheets were firstly synthesized templating by both large and small micelles of mono-dodecyl phosphate. The obtained hollow monetite microspheres had a diameter of 10 ∼ 30 μm with a specific surface area of 86.76 m2 g−1 and a total pore volume of 0.466 cm3 g−1. The monetite nanosheets which were assembly units of the hollow microspheres possessed many mesopores with a pore size of about 25 nm. The mesoporous hollow monetite microspheres had adsorption capacity of lead ions and vancomycin as high as 1435.6 mg g−1 and 518 mg g−1, respectively. And the vancomycin loaded monetite microspheres exhibited a pH-responsive drug release behavior. The mesoporous hollow monetite microspheres have great potential in contaminants adsorbents and drug carriers.

Lead/cadmium-free near-infrared multifunctional nanoplatform for deep-tissue bimodal imaging and drug delivery

Well-designed multifunctional nanoplatforms integrating diagnosis and therapy capabilities are of significant importance in the emerging research area of theranostics, which is expected to have great impact on future medicine. Herein, we rationally designed and engineered a multifunctional NaGdF4:Nd3+@mSiO2 nanoplatform by loading ultrasmall NaGdF4:Nd3+ nanoparticles (∼4.1 nm in diameter) into relatively large-channel mesoporous SiO2 (mSiO2) nanospheres for the first time. Thanks to the unique combination of paramagnetic property, and the capability of being excited by near infrared (NIR) light in the first biological window (NIR-I: 700–950 nm) and emitting in the second biological window (NIR-II: 1000–1350 nm) in single-type nanoparticles of NaGdF4:Nd3+, the NaGdF4:Nd3+@mSiO2 nanoplatform realizes magnetic resonance and NIR photoluminescence dual-mode tumor imaging of live mice. In particular, this NIR-I excitation and NIR-II emission property enables in vitro NIR porcine tissue photoluminescence imaging up to 12 mm in thickness. Moreover, the unique three-dimensional mesoporous structure of the nanoplatform allows the efficient loading of doxorubicin molecules (DOX, a commonly used drug model) at a high level and demonstrates pH-responsive drug release behavior that is beneficial for cancer-targeted therapy. More importantly, this NIR-II emitting nanoplatform does not contain toxic heavy metals of lead (Pb) and cadmium (Cd) usually found in NIR-emitting nanoparticles and further, comprises a highly biocompatible, protective SiO2 network. As a result, the NaGdF4:Nd3+@mSiO2 nanoplatform demonstrates much less cytotoxicity, as compared to the counterpart containing Pb and/or Cd-based quantum dots. All these features endow the multifunctional NaGdF4:Nd3+@mSiO2 nanoplatform great potential in simultaneous disease imaging diagnostics and therapeutics.

PH-responsive drug release and antibacterial activity of chitosan-coated core/shell borate glass-hydroxyapatite microspheres

Multifunctional drug delivery system that can treat bone infection and concurrently accelerate bone tissue regeneration is highly desirable. In this study, we developed a pH-responsive local drug carrier in which a core/shell microsphere consisting of a borate glass core and a mesoporous hydroxyapatite HA shell (BG-HA) was coated with glutaraldehyde-crosslinked chitosan (CS). At neutral pH, a negligible concentration of vancomycin was released from the BG-HA@CS microspheres. However, in an acidic environment, the pores on the HA shell were uncapped due to the swelling of CS, thus accelerating the drug release. The advantage of the BG-HA@CS was evidenced by comparing with HA@CS that was prepared by fully converting borate glass followed by CS coating. The dissolution of the unconverted borate glass core upon immersing in PBS led to an increase in the local pH. This change of pH regulated the swelling/de-swelling behaviours of CS, thereby realizing more sustained drug release. Furthermore, it revealed that the vancomycin-loaded BG-HA@CS provided highly effective antibacterial activity against S. aureus and E. coli, while the vancomycin-loaded HA@CS did not show inhibitory effect on E. coli. The results indicated that the BG-HA@CS would be a promising multifunctional delivery system that can achieve self-regulated drug release, control the acidic environment of bone infection sites and promote bone tissue regeneration.

Combined Chemo-Immuno-Photothermal Therapy for Effective Cancer Treatment via an All-in-One and One-for-All Nanoplatform.

Tumor metastasis and recurrence are recognized to be the main causes of failure in cancer treatment. To address these issues, an "all in one" and "one for all" nanoplatform was established for combined "chemo-immuno-photothermal" therapy with the expectation to improve the antitumor efficacy. Herein, Docetaxel (DTX, a chemo-agent) and cynomorium songaricum polysaccharide (CSP, an immunomodulator) were loaded into zein nanoparticles coated by a green tea polyphenols/iron coordination complex (GTP/FeIII, a photothermal agent). From the result, the obtained nanoplatform denoted as DTX-loaded Zein/CSP-GTP/FeIII NPs was spherical in morphology with an average particle size of 274 nm, and achieved pH-responsive drug release. Moreover, the nanoplatform exhibited excellent photothermal effect both in vitro and in vivo. It was also observed that the nanoparticles could be effectively up take by tumor cells and inhibited their migration. From the results of the in vivo experiment, this nanoplatform could completely eliminate the primary tumors, prevent tumor relapses on LLC (Lewis lung cancer) tumor models, and significantly inhibit metastasis on 4T1 (murine breast cancer) tumor models. The underlying mechanism was also explored. It was discovered that this nanoplatform could induce a strong ICD effect and promote the release of damage-associated molecular patterns (DAMPs) including CRT, ATP, and HMGB1 by the dying tumor cells. And the CSP could assist the DAMPs in inducing the maturation of dendritic cells (DCs) and facilitate the intratumoral infiltration of T lymphocytes to clear up the residual or disseminated tumor cells. In summary, this study demonstrated that the DTX-loaded Zein/CSP-GTP/FeIII is a promising nanoplatform to completely inhibit tumor metastasis and recurrence.