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Metastatic tumors are the main cause of cancer-related death, as the invading cancer cells disrupt normal functions of distant organs and are nearly impossible to eradicate by traditional cancer therapeutics. This is of special concern when the cancer has created multiple metastases and extensive surgery would be too dangerous to execute. Therefore, combination chemotherapy is often the selected treatment form. However, drug cocktails often have severe adverse effects on healthy cells, whereby the development of targeted drug delivery could minimize side-effects of drugs and increase the efficacy of the combination therapy. In this study, we utilized the folate antagonist methotrexate (MTX) as targeting ligand conjugated onto mesoporous silica nanoparticles (MSNs) for selective eradication of folate receptor-expressing invasive thyroid cancer cells. The MSNs was subsequently loaded with the drug fingolimod (FTY720), which has previously been shown to efficiently inhibit proliferation and invasion of aggressive thyroid cancer cells. To assess the efficiency of our carrier system, comprehensive in vitro methods were employed; including flow cytometry, confocal microscopy, viability assays, invasion assay, and label-free imaging techniques. The in vitro results show that MTX-conjugated and FTY720-loaded MSNs potently attenuated both the proliferation and invasion of the cancerous thyroid cells while keeping the off-target effects in normal thyroid cells reasonably low. For a more physiologically relevant in vivo approach we utilized the chick chorioallantoic membrane (CAM) assay, showing decreased invasive behavior of the thyroid derived xenografts and an increased necrotic phenotype compared to tumors that received the free drug cocktail. Thus, the developed multidrug-loaded MSNs effectively induced apoptosis and immobilization of invasive thyroid cancer cells, and could potentially be used as a carrier system for targeted drug delivery for the treatment of diverse forms of aggressive cancers that expresses folate receptors.

Nanogels (Ng) are crosslinked polymer-based hydrogel nanoparticles considered to be next-generation drug delivery systems due to their superior properties, including high drug loading capacity, low toxicity, and stimuli responsiveness. In this study, dually thermo-pH-responsive plasmonic nanogel (AuNP@Ng) was synthesized by grafting poly (N-isopropyl acrylamide) (PNIPAM) to chitosan (CS) in the presence of a chemical crosslinker to serve as a drug carrier system. The nanogel was further incorporated with gold nanoparticles (AuNP) to provide simultaneous drug delivery and photothermal therapy (PTT). Curcumin's (Cur) low water solubility and low bioavailability are the biggest obstacles to effective use of curcumin for anticancer therapy, and these obstacles can be overcome by utilizing an efficient delivery system. Therefore, curcumin was chosen as a model drug to be loaded into the nanogel for enhancing the anticancer efficiency, and further, its therapeutic efficiency was enhanced by PTT of the formulated AuNP@Ng. Thorough characterization of Ng based on CS and PNIPAM was conducted to confirm successful synthesis. Furthermore, photothermal properties and swelling ratio of fabricated nanoparticles were evaluated. Morphology and size measurements of nanogel were determined by transmission electron microscopy (TEM), scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). Nanogel was found to have a hydrodynamic size of ~167 nm and exhibited sustained release of curcumin up to 72 h with dual thermo-pH responsive drug release behavior, as examined under different temperature and pH conditions. Cytocompatibility of plasmonic nanogel was evaluated on MDA-MB-231 human breast cancer and non-tumorigenic MCF 10A cell lines, and the findings indicated the nanogel formulation to be cytocompatible. Nanoparticle uptake studies showed high internalization of nanoparticles in cancer cells when compared with non-tumorigenic cells and confocal microscopy further demonstrated that AuNP@Ng were internalized into the MDA-MB-231 cancer cells via endosomal route. In vitro cytotoxicity studies revealed dose-dependent and time-dependent drug delivery of curcumin loaded AuNP@Ng/Cur. Furthermore, the developed nanoparticles showed an improved chemotherapy efficacy when irradiated with near-infrared (NIR) laser (808 nm) in vitro. This work revealed that synthesized plasmonic nanogel loaded with curcumin (AuNP@Ng/Cur) can act as stimuli-responsive nanocarriers, having potential for dual therapy i.e., delivery of hydrophobic drug and photothermal therapy.

Cancer is an exceptionally confounding disease that demands the development of powerful drug/drugs, without inducing heavy adverse side effects. Thus, different approaches have been applied to improve the targeted delivery of cancer drugs: for example by using nanocarriers. However, nanocarriers are foreign materials, which need further validation for their biocompatibility and biodegradability. In this study, we have chemically conjugated the hydrophilic anticancer drug doxorubicin (DOX) with the hydrophobic drug paclitaxel (PTX) through a redox-sensitive disulfide bond, abbreviated to DOX-S-S-PTX. Subsequently, due to its amphiphilic characterization, the prodrug can self-assemble into nanoparticles under microfluidic nanoprecipitation. These novel prodrug nanoparticles have a super-high drug loading degree of 89%, which is impossible to achieve by any nanocarrier systems, and can be tailored to 180 nm to deliver themselves to the target, and release DOX and PTX under redox conditions, which are often found in cancer cells. By evaluating cell viability in MDA-MB-231, MDA-MB-231/ADR and MEF cell lines, we observed that the prodrug nanoparticles effectively killed the cancer cells, and selectively conquered the MDA-MB-231/ADR. Meanwhile, MEF cells were spared due to their lack of a redox condition. The cell interaction results show that the reduced intermediate of the prodrug can also bind to parent drug biological targets. The hemolysis results show that the nanoparticles are biocompatible in blood. Computer modelling suggested that the prodrug is unlikely to bind to biological targets that parent drugs still strongly interact with. Finally, we confirm that the prodrug nanoparticles have no therapeutic effect in blood or healthy cells, but can selectively eliminate the cancer cells that meet the redox conditions to cleave the disulfide bond and release the drugs DOX and PTX.

Hierarchically organized hybrid MOF particles were developed to meet the stable luminescence requirements of lanthanide complexes for applications in biological media. Anionic terbium (Tb) complexes sensitized by tridentate pyridine-tetrazolate (pytz) ligands (i.e. Tb(pytz)3) were encapsulated in zeolitic imidazolate framework-8 (ZIF-8) nanoparticles (∼150 nm). TIF-1Zn (Zn(DMBIM)2) frameworks were then hybridized with ZIF-8 by the mediation of a hydrophobic ligand, i.e. DMBIM (5,6-dimethylbenzimidazole). A bio-inspired polymer, i.e. polydopamine, was utilized for imparting the particles with hydrophilicity and functionalization ability. An unprecedentedly high quantum yield (82.0%) and luminescence stability in PBS buffer were realized by the hierarchical structure.

Cancer stem cells (CSCs) are a challenge in cancer treatment due to their therapy resistance. We demonstrated that enhanced Notch signaling in breast cancer promotes self-renewal of CSCs that display high glycolytic activity and aggressive hormone-independent tumor growth in vivo. We took advantage of the glycolytic phenotype and the dependence on Notch activity of the CSCs and designed nanoparticles to target the CSCs. Mesoporous silica nanoparticles were functionalized with glucose moieties and loaded with a γ-secretase inhibitor, a potent interceptor of Notch signaling. Cancer cells and CSCs in vitro and in vivo efficiently internalized these particles, and particle uptake correlated with the glycolytic profile of the cells. Nanoparticle treatment of breast cancer transplants on chick embryo chorioallantoic membranes efficiently reduced the cancer stem cell population of the tumor. Our data reveal that specific CSC characteristics can be utilized in nanoparticle design to improve CSC-targeted drug delivery and therapy. publishedVersion

The supplementation of stem cell culture medium with fetal bovine serum (FBS) for maintenance and propagation of cell lines in vitro is associated with immunogenicity and disease transmission by prions, bacteria, and viruses. Therefore, establishing xenogenic-free cell culture media for the benefit of rational testing conditions for stem cells in terms of eliminating the disadvantages is essential. In parallel, a number of investigations have been carried out on nanoparticle (NP) aided stem cell-based therapies. To use NP-integrated stem cell therapy in clinical applications, NP behavior in xenogenic-free stem cell cultures needs to be understood in detail. Mesoporous silica nanoparticles (MSN) are profusely used in biomedical applications and have also shown great potential in stem cell therapies. One of the strategies to make them compatible with stem cell therapy is to alter their surface functionalization. In line with this notion, the main interest of the present investigation was to study the impact of human serum albumin (HSA) association with differently surface-modified MSN, and rationalize the MSN utilization in xenogenic-free stem cell culture by employing C2C12 myogenic progenitor cells as a model system. Our results revealed that HSA coating on differently surface-modified MSN is a promising strategy to improve the colloidal stability of MSN, stem cell viability, and imparts no adverse effects on the differentiation of stem cells.

Mesoporous silica nanoparticles (MSNs) are extensively explored as drug delivery systems, but in depth understanding of design-toxicity relationships is still scarce. We used zebrafish (Danio rerio) embryos to study toxicity profiles of differently surface functionalized MSNs. Embryos with the chorion membrane intact, or dechoroniated embryos, were incubated or microinjected with amino (NH2-MSNs), polyethyleneimine (PEI-MSNs), succinic acid (SUCC-MSNs) or polyethyleneglycol (PEG-MSNs) functionalized MSNs. Toxicity was assessed by viability and cardiovascular function. NH2-MSNs, SUCC-MSNs and PEG-MSNs were well tolerated, 50 µg/ml PEI-MSNs induced 100% lethality 48 hours post fertilization (hpf). Dechoroniated embryos were more sensitive and 10 µg/ml PEI-MSNs reduced viability to 5% at 96hpf. Sensitivity to PEG- and SUCC-, but not NH2-MSNs, was also enhanced. Typically cardiovascular toxicity was evident prior to lethality. Confocal microscopy revealed that PEI-MSNs penetrated into the embryos whereas PEG-, NH2- and SUCC-MSNs remained aggregated on the skin surface. Direct exposure of inner organs by microinjecting NH2-MSNs and PEI-MSNs demonstrated that the particles displayed similar toxicity indicating that functionalization affects the toxicity profile by influencing penetrance through biological barriers. The data emphasize the need for careful analyses of toxicity mechanisms in relevant models and constitute an important knowledge step towards the development of safer and sustainable nanotherapies

Nanomedicine is gaining ground worldwide in therapy and diagnostics. Novel nanoscopic imaging probes serve as imaging tools for studying dynamic biological processes in vitro and in vivo. To allow detectability in the physiological environment, the nanostructure-based probes need to be either inherently detectable by biomedical imaging techniques, or serve as carriers for existing imaging agents. In this study, the potential of mesoporous silica nanoparticles carrying commercially available fluorochromes as self-regenerating cell labels for long-term cellular tracking is investigated. The particle surface is organically modified for enhanced cellular uptake, the fluorescence intensity of labeled cells is followed over time both in vitro and in vivo. The particles are not exocytosed and particles which escaped cells due to cell injury or death are degraded and no labeling of nontargeted cell populations are observed. The labeling efficiency is significantly improved as compared to that of quantum dots of similar emission wavelength. Labeled human breast cancer cells are xenotransplanted in nude mice, and the fluorescent cells can be detected in vivo for a period of 1 month. Moreover, ex vivo analysis reveals fluorescently labeled metastatic colonies in lymph node and rib, highlighting the capability of the developed probes for tracking of metastasis. Mesoporous silica nanoparticles (MSNs) as carriers for optical imaging agents facilitate long-term monitoring of tumor progression and tracking of metastatic cells. MSNs are surface modified for efficient cellular labeling and incorporated with commercially available, affordable fluorescent dyes via different means. The optimized MSN-dye formulation preserves fluorescence intensity signal retention in vivo for a period of 1 month.