Core-shell semiconductor nanocrystals: Effect of composition, size, surface coatings on their optical properties, toxicity, and pharmacokinetics

Quantum dots are semiconducting nanocrystals that exhibit extraordinary optical properties. QD have shown higher photostability compared to standard organic dye type probes. Therefore, they have been heavily explored in the biomedical field. This review will discuss the different approaches to synthesis, solubilise and functionalise QD. Their main biomedical applications in imaging and photodynamic therapy will be highlighted. Finally, QD biodistribution profile and in vivo toxicity will be discussed

Real-time monitoring of magnetic drug targeting using fibered confocal fluorescence microscopy

Magnetic drug targeting has been proposed as means of concentrating therapeutic agents at a target site and the success of this approach has been demonstrated in a number of studies. However, the behavior of magnetic carriers in blood vessels and tumor microcirculation still remains unclear. In this work, we utilized polymeric magnetic nanocapsules (m-NCs) for magnetic targeting in tumors and dynamically visualized them within blood vessels and tumor tissues before, during and after magnetic field exposure using fibered confocal fluorescence microscopy (FCFM). Our results suggested that the distribution of m-NCs within tumor vasculature changed dramatically, but in a reversible way, upon application and removal of a magnetic field. The m-NCs were concentrated and stayed as clusters near a blood vessel wall when tumors were exposed to a magnetic field but without rupturing the blood vessel. The obtained FCFM images provided in vivo in situ microvascular observations of m-NCs upon magnetic targeting with high spatial resolution but minimally invasive surgical procedures. This proof-of-concept descriptive study in mice is envisaged to track and quantify nanoparticles in vivo in a non-invasive manner at microscopic resolution

Triple-Modal Imaging of Magnetically-Targeted Nanocapsules in Solid Tumours In Vivo

Triple-modal imaging magnetic nanocapsules, encapsulating hydrophobic superparamagnetic iron oxide nanoparticles, are formulated and used to magnetically target solid tumours after intravenous administration in tumour-bearing mice. The engineered magnetic polymeric nanocapsules m-NCs are ~200 nm in size with negative Zeta potential and shown to be spherical in shape. The loading efficiency of superparamagnetic iron oxide nanoparticles in the m-NC was ~100%. Up to ~3- and ~2.2-fold increase in tumour uptake at 1 and 24 h was achieved, when a static magnetic field was applied to the tumour for 1 hour. m-NCs, with multiple imaging probes (e.g. indocyanine green, superparamagnetic iron oxide nanoparticles and indium-111), were capable of triple-modal imaging (fluorescence/magnetic resonance/nuclear imaging) in vivo. Using triple-modal imaging is to overcome the intrinsic limitations of single modality imaging and provides complementary information on the spatial distribution of the nanocarrier within the tumour. The significant findings of this study could open up new research perspectives in using novel magnetically-responsive nanomaterials in magnetic-drug targeting combined with multi-modal imaging

Design of Cationic Multi-Walled Carbon Nanotubes as Efficient siRNA Vectors for Lung Cancer Xenograft Eradication

Polo-Like Kinase (PLK1) has been identified as a potential target in cancer gene therapy via chemical or genetic inhibitory approaches. The biomedical applications of chemically functionalized carbon nanotubes (f-CNTs) in cancer therapy have been studied due to their ability to efficiently deliver siRNA intracellularly. In this study, we established the capacity of cationic MWNT-NH3+ to deliver the apoptotic siRNA against PLK1 (siPLK1) in Calu6 tumor xenografts by direct intratumoural injections. A direct comparison with cationic liposomes was made. This study validates the PLK1 gene as a potential target in cancer gene therapy including lung cancer, as demonstrated by the therapeutic efficacy of siPLK1:MWNT-NH3+ complexes and their ability to significantly improve animal survival. Biological analysis of the siPLK1:MWNT-NH3+ treated tumors by RT-PCR and Western blot, in addition to TUNEL staining confirmed the biological functionality of the siRNA intratumourally, suggesting that tumor eradication was due to PLK1 knockdown. Furthermore, by using a fluorescently labelled, non-coding siRNA sequence complexed with MWNT-NH3+, we established for the first time that the improved therapeutic efficacy observed in f-CNT-based siRNA delivery is directly proportional to the enhanced siRNA retention in the solid tumor and subsequent uptake by tumor cells after local administration in vivo

Press reslease from the Premier and Tourism Minister, Mr Dunstan: New amenity block for Moonta Bay Caravan Park

Getting rid of the tubes: An assessment of the retention of functionalized multi-walled carbon nanotubes (MWNTs) in the organs of mice was carried out using single photon emission computed tomography and quantitative scintigraphy (see scheme). Increasing the degree of functionalization on MWNTs enhanced renal clearance, while lower functionalization promoted reticuloendethelial system accumulation

Magnetic drug targeting: Preclinical in vivo studies, mathematical modeling, and extrapolation to humans

A sound theoretical rationale for the design of a magnetic nanocarrier capable of magnetic capture in vivo after intravenous administration could help elucidate the parameters necessary for in vivo magnetic tumor targeting. In this work, we utilized our long-circulating polymeric magnetic nanocarriers, encapsulating increasing amounts of superparamagnetic iron oxide nanoparticles (SPIONs) in a biocompatible oil carrier, to study the effects of SPION loading and of applied magnetic field strength on magnetic tumor targeting in CT26 tumor-bearing mice. Under controlled conditions, the in vivo magnetic targeting was quantified and found to be directly proportional to SPION loading and magnetic field strength. Highest SPION loading, however, resulted in a reduced blood circulation time and a plateauing of the magnetic targeting. Mathematical modeling was undertaken to compute the in vivo magnetic, viscoelastic, convective, and diffusive forces acting on the nanocapsules (NCs) in accordance with the Nacev–Shapiro construct, and this was then used to extrapolate to the expected behavior in humans. The model predicted that in the latter case, the NCs and magnetic forces applied here would have been sufficient to achieve successful targeting in humans. Lastly, an in vivo murine tumor growth delay study was performed using docetaxel (DTX)-encapsulated NCs. Magnetic targeting was found to offer enhanced therapeutic efficacy and improve mice survival compared to passive targeting at drug doses of ca. 5–8 mg of DTX/kg. This is, to our knowledge, the first study that truly bridges the gap between preclinical experiments and clinical translation in the field of magnetic drug targeting

Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A)

We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p- substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement

In vitro potency, in vitro and in vivo efficacy of liposomal alendronate in combination with γδ T cell immunotherapy in mice

Nitrogen-containing bisphosphonate (N-BP), including zoledronic acid (ZOL) and alendronate (ALD), have been proposed as sensitisers in γδ T cell immunotherapy in pre-clinical and clinical studies. Therapeutic efficacy of N-BPs is hampered by their rapid renal excretion and high affinity for bone. Liposomal formulations of N-BP have been proposed to improve accumulation in solid tumours. Liposomal alendronate (L-ALD) has been suggested as a suitable alternative to liposomal ZOL (L-ZOL), due to unexpected mice death experienced in pre-clinical studies with the latter. Only one study so far has proven the therapeutic efficacy of L-ALD, in combination with γδ T cell immunotherapy, after intraperitoneal administration of γδ T cell resulting in delayed growth of ovarian cancer in mice. This study aims to assess the in vitro efficacy of L-ALD, in combination with γδ T cell immunotherapy, in a range of cancerous cell lines, using L-ZOL as a comparator. The therapeutic efficacy was tested in a pseudo-metastatic lung mouse model, following intravenous injection of γδ T cell, L-ALD or the combination. In vivo biocompatibility and organ biodistribution studies of L-BPs were undertaken simultaneously. Higher concentrations of L-ALD (40–60 μM) than L-ZOL (3–10 μM) were required to produce a comparative reduction in cell viability in vitro, when used in combination with γδ T cells. Significant inhibition of tumour growth was observed after treatment with both L-ALD and γδ T cells in pseudo-metastatic lung melanoma tumour-bearing mice after tail vein injection of both treatments, suggesting that therapeutically relevant concentrations of L-ALD and γδ T cell could be achieved in the tumour sites, resulting in significant delay in tumour growth

Docetaxel-loaded liposomes: The effect of lipid composition and purification on drug encapsulation and in vitro toxicity

Docetaxel (DTX)-loaded liposomes have been formulated to overcome DTX solubility issue, improve its efficacy and reduce its toxicity. This study investigated the effect of steric stabilisation, varying liposome composition, and lipid:drug molar ratio on drug loading and on the physicochemical properties of the DTX-loaded liposomes. Size exclusion chromatography (SEC) was used to remove free DTX from the liposomal formulation, and its impact on drug loading and in vitro cytotoxicity was also evaluated. Liposomes composed of fluid, unsaturated lipid (DOPC:Chol:DSPE-PEG2000) showed the highest DTX loading compared to rigid, saturated lipids (DPPC:Chol:DSPE-PEG2000 and DSPC:Chol:DSPE-PEG2000). The inclusion of PEG showed a minimum effect on DTX encapsulation. Decreasing lipid:drug molar ratio from 40:1 to 5:1 led to an improvement in the loading capacities of DOPC-based liposomes only. Up to 3.6-fold decrease in drug loading was observed after liposome purification, likely due to the loss of adsorbed and loosely entrapped DTX in the SEC column. Our in vitro toxicity results in PC3 monolayer showed that non-purified, DTX-loaded DOPC:Chol liposomes were initially (24h) more potent than the purified ones, due to the fast action of the surface- adsorbed drug. However, we hypothesize that over time (48 and 72h) the purified, DTX-loaded DOPC:Chol liposomes became more toxic due to high intracellular release of encapsulated DTX. Finally, our cytotoxicity results in PC3 spheroids showed the superior activity of DTX-loaded liposomes compared to free DTX, which could overcome the DTX poor tissue penetration, drug resistance, and improve its therapeutic efficacy following systemic administration

Engineering thermosensitive liposome-nanoparticle hybrids loaded with doxorubicin for heat-triggered drug release

The engineering of responsive multifunctional delivery systems that combine therapeutic and diagnostic (theranostic) capabilities holds great promise and interest. We describe the design of thermosensitive liposome-nanoparticle (NP) hybrids that can modulate drug release in response to external heating stimulus. These hybrid systems were successfully engineered by the incorporation of gold, silver, and iron oxide NPs into the lipid bilayer of lysolipid-containing thermosensitive liposomes (LTSL). Structural characterization of LTSL-NP hybrids using cryo-EM and AFM revealed the incorporation of metallic NPs into the lipid membranes without compromising doxorubicin loading and retention capability. The presence of metallic NPs in the lipid bilayer reinforced bilayer retention and offered a nanoparticle concentration-dependent modulation of drug release in response to external heating. In conclusion, LTSL-NP hybrids represent a promising versatile platform based on LTSL liposomes that could further utilize the properties of the embedded NPs for multifunctional theranostic applications