pH-sensitive Nanosystems Research Articles

Rapid Microwave-Assisted Synthesis of pH-Sensitive Carbon-Based Nanoparticles for the Controlled Release of Doxorubicin to Cancer Cells.

Carbon-based nanoparticles (CNPs) are a new type of interesting nanomaterials applied in various pharmaceutical fields due to their outstanding biocompatible properties. Novel pH-sensitive CNPs were rapidly synthesized within 1min by microwave-assisted technique for doxorubicin (DOX) delivery into five cancer cell lines, including breast cancer (BT-474 and MDA-MB-231 cell lines), colon cancer (HCT and HT29 cell lines), and cervical cancer (HeLa cell lines). CNPs and DOX-loaded CNPs (CNPs-DOX) had nano-size of 11.66 ± 2.32nm and 43.24 ± 13.25nm, respectively. DOX could be self-assembled with CNPs in phosphate buffer solution at pH 7.4 through electrostatic interaction, exhibiting high loading efficiency at 85.82%. The release of DOX from CNPs-DOX at pH 5.0, often observed in the tumor, was nearly two times greater than the release at physiological condition pH 7.4. Furthermore, the anticancer activity of CNPs-DOX was significantly enhanced compared to free DOX in five cancer cell lines. CNPs-DOX could induce cell death through apoptosis induction in MDA-MB-231 cells. The findings revealed that CNPs-DOX exhibited a promising pH-sensitive nano-system as a drug delivery carrier for cancer treatment.

Kinetics and Mechanism of Camptothecin Release from Transferrin-Gated Mesoporous Silica Nanoparticles through a pH-Responsive Surface Linker.

Stimuli-responsive nanomaterials have emerged as a promising strategy for inclusion in anticancer therapy. In particular, pH-responsive silica nanocarriers have been studied to provide controlled drug delivery in acidic tumor microenvironments. However, the intracellular microenvironment that the nanosystem must face has an impact on the anticancer effect; therefore, the design of the nanocarrier and the mechanisms that govern drug release play a crucial role in optimizing efficacy. Here, we synthesized and characterized mesoporous silica nanoparticles with transferrin conjugated on their surface via a pH-sensitive imine bond (MSN-Tf) to assess camptothecin (CPT) loading and release. The results showed that CPT-loaded MSN-Tf (MSN-Tf@CPT) had a size of ca. 90 nm, a zeta potential of -18.9 mV, and a loaded content of 13.4%. The release kinetic data best fit a first-order model, and the predominant mechanism was Fickian diffusion. Additionally, a three-parameter model demonstrated the drug-matrix interaction and impact of transferrin in controlling the release of CPT from the nanocarrier. Taken together, these results provide new insights into the behavior of a hydrophobic drug released from a pH-sensitive nanosystem.

Smart chitosan–folate hybrid magnetic nanoparticles for targeted delivery of doxorubicin to osteosarcoma cells

Chitosan (CS)-based pH-sensitive nanocomposites were fabricated for the targeted delivery of doxorubicin (DOX) to osteosarcoma cells. To prepare the nanocomposite, CS was functionalized with succinic anhydride (SA) (CS-SA). CS-folic acid (FA) conjugates were produced by the conjugation of CS with FA via an amide bond. Next, Fe3O4 magnetic nanoparticles (MNPs) ferrofluid was fabricated, and nanocomposite was produced using MNPs and synthesized CS–SA/CS-FA and CS–SA via an inclusion formation between −COOH groups of CS-SA and hydroxyl groups of Fe3O4. Finally, DOX molecules were loaded onto the nanocomposites. The nanocomposites were characterized through FT-IR, DLS, XRD, VSM, TEM, and UV-Vis spectroscopy analyses. DOX release profile at various pHs indicated an enhanced release of DOX in acidic conditions. The cytotoxicity assay demonstrated that the nanocarriers alone were cytocompatible on cells examined. The MG-63 cells, which partly express the folate receptors (FRs), particularly FR-α, showed meaningfully higher cellular uptake of the DOX-loaded CS-FA/CS-SA@MNPs than the FR-negative lung cancer A549 cells. The DOX-loaded CS-FA/CS-SA-MNPs could induce significant cytotoxicity in the MG-63 cells but not in A549 cells. Based on these findings, the DOX-loaded CS-FA/ CS-SA-MNPs might be considered a smart pH-sensitive nanosystem for the targeted delivery of anticancer agents to osteosarcoma 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.

Cancer-cell-biomimetic nanoparticles systemically eliminate hypoxia tumors by synergistic chemotherapy and checkpoint blockade immunotherapy

Checkpoint blockade-based immunotherapy has shown unprecedented effect in cancer treatments, but its clinical implementation has been restricted by the low host antitumor response rate. Recently, chemotherapy is well recognized to activate the immune system during some chemotherapeutics-mediated tumor eradication. The enhancement of immune response during chemotherapy might further improve the therapeutic efficiency through the synergetic mechanism. Herein, a synergistic antitumor platform (designated as BMS/RA@CC-Liposome) was constructed by utilizing CT26 cancer-cell-biomimetic nanoparticles that combined chemotherapeutic drug (RA-V) and PD-1/PD-L1 blockade inhibitor (BMS-202) to remarkably enhance antitumor immunity. In this study, the cyclopeptide RA-V as chemotherapeutic drugs directly killing tumor cells and BMS-202 as anti-PD agents eliciting antitumor immune responses were co-encapsulated in a pH-sensitive nanosystem. To achieve the cell-specific targeting drug delivery, the combination therapy nanosystem was functionalized with cancer cell membrane camouflage. The biomimetic drug delivery system perfectly disguised as endogenous substances, and realized elongated blood circulation due to anti-phagocytosis capability. Moreover, the BMS/RA@CC-Liposome also achieved the selective targeting of CT26 cells by taking advantage of the inherent homologous adhesion property of tumor cells. The in vitro and in vivo experiments revealed that the BMS/RA@CC-Liposome realized PD-1/PD-L1 blockade-induced immune response, RA-V-induced PD-L1 down-regulation and apoptosis in cancer cells. Such a system combining the advantages of chemotherapy and checkpoint blockade-based immunotherapy to create an immunogenic tumor microenvironment systemically, demonstrated improved therapeutic efficacy against hypoxic tumor cells and offers an alternative strategy based on the immunology of the PD-1/PD-L1 pathway.

Dasatinib self-assembled nanoparticles decorated with hyaluronic acid for targeted treatment of tumors to overcome multidrug resistance

Multidrug resistance (MDR) and lack of targeting specificity are the main reasons why traditional drug therapies fail and produce toxic side effects in cancer chemotherapy. In order to increase targeting specificity and maximize therapeutic efficacy, new intelligent drug delivery systems are needed. In this study, we prepared the hyaluronic acid (HA) conjugated dasatinib (DAS) and D-α-tocopherol acid polyethylene glycolsuccinate (TPGS) copolymer nanoparticles (THD-NPs). The water solubility of the hydrophobic drug DAS was improved by chemically linking with HA. HA can bind to the over-expressed CD44 protein of tumor cells to increase targeting specificity, TPGS can inhibit the activity of P-glycoprotein (P-gp), and increase the intracellular accumulation of drugs. The prepared drug-loaded nanoparticle has a particle size of 82.23 ± 1.07 nm with good in vitro stability. Our in vitro studies showed that THD-NPs can be released more rapidly in a weakly acidic environment (pH = 5.5) than in a normal physiological environment (pH = 7.4), which can realize the selective release of nanoparticles in tumor cells. Compared to free drugs, THD-NPs showed more efficient cellular uptake, effectively increased the cytotoxic effect of DAS on nasopharyngeal carcinoma HNE1 cells drug resistance HNE1/DDP cells and increased the accumulation of drugs in HNE1/DDP cells, which may be due to the inhibitory effect of TPGS on the efflux function of P-gp. In vivo experiments showed that THD-NPs can effectively inhibit tumor growth without obvious side effects. In conclusion, the targeted and pH-sensitive nanosystem, we designed has great potential to overcome drug resistance and increase therapeutic effects in cancer treatment.

PH-Sensitive Nanomedicine for Treating Gynaecological Cancers

Emergence of various nanoscale drug carrier platforms as Drug Delivery Systems (DDS) has revolutionized the field of medicine.Nonetheless, theside-effects due to non-specific distribution of anticancer therapeutics in normal, healthy tissues remain to be a prime pitfall in curing cancers. Therefore, to achieve a better therapeutic efficacy, the use of a target-specific delivery, combined with a stimuli-responsive nanocarrier system, particularly pH-sensitive nanosystems offer an attractive strategy. Targeted drug delivery through pH-sensitive nanosystems offer the potential to enhance the therapeutic index of anticancer agents, either by increasing the drug concentration in tumor cells and/or by decreasing the exposure in normal host tissues. Therefore, nanoscale-based drug delivery through pH-sensitive nanosystems seem to be a boon for treating gynaecological cancers (as well as other cancers) without side-effects or with least harm to normal healthy tissues.

Panacea for Gynaecological Cancers: pH-Sensitive Nanomedicine

Emergence of various nanoscale drug carrier platforms as Drug Delivery Systems (DDS) has revolutionized the field of medicine. Nonetheless, the side-effects due to non-specific distribution of anticancer therapeutics in normal, healthy tissues remains to be a prime pitfall in curing cancers. Therefore, to achieve a better therapeutic efficacy, the use of a target-specific delivery, combined with a stimuli-responsive nanocarrier system, particularly pH-sensitive nanosystems offer an attractive strategy. Targeted drug delivery through pH-sensitive nanosystems offer the potential to enhance the therapeutic index of anticancer agents, either by increasing the drug concentration in tumor cells and/or by decreasing the exposure in normal host tissues. Therefore, nanoscale-based drug delivery through pH-sensitive nanosystems seem to be a boon for treating gynaecological cancers (as well as other cancers) without side-effects or with least harm to normal healthy tissues.

A Beacon for Gynaecological Cancers Patients: pH-Sensitive Nano medicine

Emergence of various Nano scale drug carrier platforms as Drug Delivery Systems (DDS) has revolutionized the field of medicine. Nonetheless, the side-effects due to non-specific distribution of anticancer therapeutics in normal, healthy tissues remain to be a prime pitfall in curing cancers. Therefore, to achieve a better therapeutic efficacy, the use of a target-specific delivery, combined with a stimuli-responsive Nano carrier system, particularly pH-sensitive Nano systems offer an attractive strategy. Targeted drug delivery through pH-sensitive Nano systems offer the potential to enhance the therapeutic index of anticancer agents, either by increasing the drug concentration in tumour cells and/or by decreasing the exposure in normal host tissues. Therefore, Nano scale-based drug delivery through pH-sensitive Nano systems seem to be a boon for treating gynaecological cancers (as well as other cancers) without side-effects or with least harm to normal healthy tissues.

Tandem activated photodynamic and chemotherapy: Using pH-Sensitive nanosystems to realize different tumour distributions of photosensitizer/prodrug for amplified combination therapy

Photodynamic therapy (PDT) combined with hypoxia-activated prodrugs to overcome hypoxia environment has been recently explored as a promising clinical modality for cancer therapy. Nevertheless, delivering these two therapeutic agents together to different tumour areas that possess a number of biological barriers remains a considerable challenge. Herein, we used the semiconducting polyelectrolyte-based zwitterionic photosensitizer (PFNS) to modify the surface of upconversion nanoparticles (NPs) and prepare near-infrared (NIR) light-responsive PDT agents (UCNP@PFNS). A pH-sensitive Mn-Ca3(PO4)2 (MnCaP) layer was further coated onto UCNP@PFNS with the hypoxia-activated prodrug AQ4N incorporated inside. The final nanocomposites exhibited a diameter of 73 nm with high stability in the blood and a remarkably enhanced permeability and retention (EPR) effect in tumours. Importantly, when these nanoparticles reached the tumour site, the acidic tumour microenvironment (pH 6.5–6.8) decomposed the MnCaP layer, releasing both UCNP@PFNS (30 nm) and AQ4N. The relatively small size of UCNP@PFNS and AQ4N satisfied the different distribution requirements in tumour and achieved a high therapeutic effect, thereby reaching an inhibition rate of as high as 83%. In addition, Mn2+ ions can be released during the decomposition of CaP, leading to a significantly increased magnetic resonance (MR) signal in the tumour site. Overall, we report a nanoparticle guided by MRI and fluorescence imaging possesses of tandem active pattern of PDT and chemotherapy, which is promising for future clinical diagnosis and treatment.

Cellular protease-mediated antitumor drug delivery by hierarchical targeting and pH-sensitive nanosystems

Cellular protease-mediated antitumor drug delivery by hierarchical targeting and pH-sensitive nanosystems

PH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer.

Multidrug resistance (MDR) remains a major challenge for providing effective chemotherapy for many cancer patients. To address this issue, we report an intelligent polymer-based drug co-delivery system which could enhance and accelerate cellular uptake and reverse MDR. The nanodrug delivery systems were constructed by encapsulating disulfiram (DSF), a P-glyco-protein (P-gp) inhibitor, into the hydrophobic core of poly(ethylene glycol)-block-poly(l-lysine) (PEG-b-PLL) block copolymer micelles, as well as 2,3-dimethylmaleic anhydride (DMA) and paclitaxel (PTX) were grafted on the side chain of l-lysine simultaneously. The surface charge of the drug-loaded micelles represents as negative in plasma (pH 7.4), which is helpful to prolong the circulation time, and in a weak acid environment of tumor tissue (pH 6.5–6.8) it can be reversed to positive, which is in favor of their entering into the cancer cells. In addition, the carrier could release DSF and PTX successively inside cells. The results of in vitro studies show that, compared to the control group, the DSF and PTX co-loaded micelles with charge reversal exhibits more effective cellular uptake and significantly increased cytotoxicity of PTX to MCF-7/ADR cells which may be due to the inhibitory effect of DSF on the efflux function of P-gp. Accordingly, such a smart pH-sensitive nanosystem, in our opinion, possesses significant potential to achieve combinational drug delivery and overcome drug resistance in cancer therapy.

A pH-Sensitive Nanosystem Based on Carboxymethyl Chitosan for Tumor-Targeted Delivery of Daunorubicin.

Nanoparticles, such as polymeric micelles, are currently regarded as effective drug delivery vehicles. In this study, a series of carboxymethyl chitosan/daunorubicin (CMCS/DNR) conjugates with macromolecular carriers of different molecular weights (MWs) were prepared and structurally characterized by Fourier transform infrared spectroscopy (FT-IR) and 1H-NMR spectroscopy. The results indicated that the MWs of the carriers greatly influenced the drug loading capacity. DNR was conjugated to the polymer via an acid-sensitive hydrazone linkage susceptible to hydrolysis at pH 5–6, thereby enabling intracellular DNR release. In aqueous media, the conjugates spontaneously formed nano-sized particles with core–shell structures (CMCS and DNR as the shell and core, respectively). Dynamic light scattering (DLS) and trans-mission electron microscopy (TEM) indicated that the prepared nanoparticles were spherical in shape with diameters of 100–200 nm and had a slight negative surface charge. In addition, in vitro drug release studies demonstrated that the micelles were highly sensitive to mild acidic conditions (pH 5.0) but remained reasonably stable at pH 6.5 and pH 7.4. Importantly, cell counting kit-8 (CCK-8) assays demonstrated that DNR-conjugated nanoparticles exerted a cytotoxic effect on HeLa cells, with the IC50 being approximately 2 times higher than that of free-DNR. Furthermore, confocal laser scanning microscopy (CLSM) revealed that the CMCS-hyd-DNR nanosystem could efficiently deliver and release DNR in the nuclei of cancer cells. Taken together, the developed CMCS based pH-sensitive nanosystem may be a potential drug delivery vehicle for cancer therapy.

PH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents.

In recent years miscellaneous smart micro/nanosystems that respond to various exogenous/endogenous stimuli including temperature, magnetic/electric field, mechanical force, ultrasound/light irradiation, redox potentials, and biomolecule concentration have been developed for targeted delivery and release of encapsulated therapeutic agents such as drugs, genes, proteins, and metal ions specifically at their required site of action. Owing to physiological differences between malignant and normal cells, or between tumors and normal tissues, pH-sensitive nanosystems represent promising smart delivery vehicles for transport and delivery of anticancer agents. Furthermore, pH-sensitive systems possess applications in delivery of metal ions and biomolecules such as proteins, insulin, etc., as well as co-delivery of cargos, dual pH-sensitive nanocarriers, dual/multi stimuli-responsive nanosystems, and even in the search for new solutions for therapy of diseases such as Alzheimer's. In order to design an optimized system, it is necessary to understand the various pH-responsive micro/nanoparticles and the different mechanisms of pH-sensitive drug release. This should be accompanied by an assessment of the theoretical and practical challenges in the design and use of these carriers. WIREs Nanomed Nanobiotechnol 2016, 8:696-716. doi: 10.1002/wnan.1389 For further resources related to this article, please visit the WIREs website.

Ligand-conjugated pH-sensitive polymeric micelles for the targeted delivery of gefitinib in lung cancers

The aim of the present study was to investigate the tumor targeting potential of a mannose-conjugated pH-sensitive nanosystem for the effective delivery of gefitinib (Gnb) to lung cancers.

A feasibility study of a pH sensitive nanomedicine using doxorubicin loaded poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol) micelles.

A polyelectrolyte block copolymer, poly(aspartic acid-graft-imidazole)-block-poly(ethylene glycol) (P(Asp-g-Im)-PEG), with several advantages such as an easy synthesis, having a high molecular weight and the buffer capacity of a zwitterionic polymer backbone compared to poly(histidine) backbones, was presently investigated to evaluate its feasibility as a pH sensitive anticancer nanomedicine. Doxorubicin (DOX) loaded P(Asp-g-Im)-PEG micelles (DPHAIM) were prepared by the bottom flask and diafiltration methods, forming stable pH sensitive nano-systems. DPHAIM with a 28% loading capacity displayed a pH dependent behavior with respect to drug release and cytotoxicity. At pH values below 7.0, the cumulative DOX release and cell cytotoxicity were increased compared to those at physiological pH. Animal imaging after intravenous administration of the micelles revealed their accumulation by passive targeting to tumor tissue compared to other normal tissues. This pH sensitive nanovehicle based on P(Asp-g-Im)-PEG is implicated as a promising anticancer nanomedicine with less toxicity on normal tissues for effective tumor treatment.

Fabrication and Intracellular Delivery of Doxorubicin/Carbonate Apatite Nanocomposites: Effect on Growth Retardation of Established Colon Tumor

In continuing search for effective treatments of cancer, the emerging model aims at efficient intracellular delivery of therapeutics into tumor cells in order to increase the drug concentration. However, the implementation of this strategy suffers from inefficient cellular uptake and drug resistance. Therefore, pH-sensitive nanosystems have recently been developed to target slightly acidic extracellular pH environment of solid tumors. The pH targeting approach is regarded as a more general strategy than conventional specific tumor cell surface targeting approaches, because the acidic tumor microclimate is most common in solid tumors. When nanosystems are combined with triggered release mechanisms in endosomal or lysosomal acidic pH along with endosomolytic capability, the nanocarriers demonstrated to overcome multidrug resistance of various tumors. Here, novel pH sensitive carbonate apatite has been fabricated to efficiently deliver anticancer drug Doxorubicin (DOX) to cancer cells, by virtue of its pH sensitivity being quite unstable under an acidic condition in endosomes and the desirable size of the resulting apatite-DOX for efficient cellular uptake as revealed by scanning electron microscopy. Florescence microscopy and flow cytometry analyses demonstrated significant uptake of drug (92%) when complexed with apatite nanoparticles. In vitro chemosensitivity assay revealed that apatite-DOX nanoparticles executed high cytotoxicity in several human cancer cell lines compared to free drugs and consequently apatite-DOX-facilitated enhanced tumor inhibitory effect was observed in colorectal tumor model within BALB/cA nude mice, thereby shedding light on their potential applications in cancer therapy.

Cyclodextrin-derived pH-responsive nanoparticles for delivery of paclitaxel

Engineering of pH-responsive nanoplatforms can be facilely achieved from acetalated α-cyclodextrin materials. The hydrolysis period of nanoparticles can be precisely tailored by using materials with various acetal types that can be easily controlled by acetalation time. These nanomaterials with pH-modulated hydrolysis and pH-triggered drug delivery capability show good biocompatibility in vitro and in vivo. Incorporation of anticancer drug paclitaxel (PTX) into newly developed pH-sensitive nanosystems leads to nanotherapeutics with significantly improved cytotoxic activity against various tumor cells. Importantly, thus formulated nanomedicines can reverse the multidrug resistance of PTX-resistant cancer cells. In vivo antitumor studies also reveal the superior of pH-sensitive nanosystems over pristine PTX and pH-insensitive PLGA nanoformulations. Moreover, comparison with other two acid-labile materials evidenced the advantages of cyclodextrin-based nanovehicles with respect to drug loading capacity, in vitro and in vivo activity as well as alleviated adverse effects. These pH-responsive nanoparticles may serve as new generation nanocarriers for drug delivery.