Mesoporous silica nanotechnology: promising advances in augmenting cancer theranostics

Abstract Owing to unique facets, such as large surface area, tunable synthesis parameters, and ease of functionalization, mesoporous silica nanoparticles (MSNs) have transpired as a worthwhile platform for cancer theranostics over the last decade. The full potential of MSNs in cancer theranostics, however, is yet to be realized. While MSNs can be employed for targeted drug delivery and imaging, their effectiveness can frequently be hindered by factors, such as biological barriers, complex tumor microenvironment, target non-specificity and ineffectiveness of individual functionalized moieties. The primary purpose of this review is to highlight technological advances such as tumor-specific, stimuli-responsive “smart” MSNs and multimodal MSN-based hybrid nanoplatforms that have the potential to overcome these limitations and improve MSN effectiveness in cancer theranostics. This article offers an extensive overview of MSN technology in cancer theranostics, outlining key directions for future research as well as the challenges that are involved in this aspect. We aim to underline the vitality of MSN technology and the relevance of current research and advancements in this field to potentially enhance clinical outcomes through the provision of more precise and focused theranostic approaches

Biogeochemistry concepts in medicine: Radiosensitizing pancreatic cancer through pathology driven biosynthesis of gold nanoparticles.

An effective strategy for overcoming radiotherapy resistance is to sequester radiosensitizing hafnium oxide or gold nanoparticles (GNPs) within tumors, but desmoplasia, but desmoplasia creates a delivery barrier impeding this approach. Here we report a radiosensitization strategy that overcomes this limitation by applying an atomic-scale agent - ionic gold - for in situ biosynthesis of GNPs within tumors. We showed that the in situ generation of GNPs occurs with higher efficiency in cancerous pancreatic cells than in non-cancerous cells and that these GNPs have high nuclear localization, resulting in the specific radiosensitization of cancer cells. Our studies in a xenograft murine model of pancreatic cancer revealed a uniform distribution of GNPs in the tumor, with insignificant gold content and low toxicity in normal organs. Radiosensitization by biosynthesized GNPs halted tumor growth for more than 30 days and was associated with a significantly higher median survival versus radiation alone (235 vs 102 days, respectively)

CXC chemokine receptor 4 (CXCR4) targeted gold nanoparticles potently enhance radiotherapy outcomes in breast cancer

CXC chemokine receptor 4 (CXCR4) is overexpressed on most breast cancer cell surfaces including triple negative breast cancer (TNBC) which lacks traditional receptor overexpression. We targeted gold nanoparticles (GNPs) to this receptor via conjugation to anti-CXCR4 antibody (cGNPs). Irradiation of cells treated with cGNPs compared to PEGylated GNPs (pGNPs) resulted in more prominent radiosensitization of MDA-MB-231 cells with abundant CXCR4 overexpression than HTB-123 cells with moderate and MCF-7 cells with minimal CXCR4 overexpression. Overexpression of CXCR4 facilitated improved cellular internalization of cGNPs and irradiation of internalized cGNPs resulted in more unrepaired DNA double strand breaks and increased the production of oxygen free radicals compared to irradiation with non-internalized pGNPs. In a murine TNBC xenograft model, CXCR4 targeting potently increased tumor regrowth delay following radiation compared to radiation in the presence of pGNPs or vehicle alone. CXCR4 targeted GNPs enhance the efficacy of TNBC radiotherapy by increasing oxidative stress and DNA damage

Evidence for nuclear internalisation of biocompatible [60]fullerene1)

Many types of nanoparticles (NPs) have been shown to internalise within mammalian cells (1), but only a few have been observed to internalise within the cell nucleus-most likely due to the tightly-regulated nuclear membrane (2). Internalisation of NPs into the nucleus is desirable for several reasons, including their use as 1. transfection agents (3), 2. drug delivery platforms for drugs that act on DNA (4), and 3. hyperthermia-inducing agents for cancer therapy using non-invasive stimulation by radiofrequency irradiation (5), magnetic-field cycling (6), or photonic activation (7). For example, derivatised NPs, including protein-functionalised quantum dots (8) and peptide-functionalised gold NPs (9), have been shown to internalise into the nucleus. For underivatised NPs, single-walled carbon nanotubes (SWNTs), have been observed by direct transmission electron microscopy (TEM) imaging to also localise in the nucleus of human macrophage cells with dose-dependent cytotoxicity (10). Fullerene C60ﾠis another classic carbon-based NP, however it was not been shown to enter the cell nucleus until recently. In particular, a water soluble derivative of C60ﾠfluorescently labelled with a small molecule fluorophore was shown to enter cell nuclei through nuclear pore complexes in liver cancer cells (11). Here, we validate the nuclear internalisation ability of the C60derivative in several other cell types, further supporting the unique intracellular biodistribution property of this specific fullerene compound

Fullerene compositions and methods for photochemical purification

In various embodiments, the present disclosure describes fullerene derivatives that are capable of photocatalytically generating reactive oxygen species in the presence of ultraviolet and/or visible light. In some embodiments, the fullerene derivatives are aminofullerenes containing a plurality of amine-terminated moieties covalently bonded to the fullerene cage. The fullerene derivatives may optionally be covalently bonded to a substrate surface for use in photocatalytic disinfection systems for removing various contaminants including, for example, bacteria, viruses, protozoa and chemical pollutants. Methods using the present fullerene and aminofullerene derivatives in various purification processes are also described herein

Biotransport kinetics and intratumoral biodistribution of malonodiserinolamide-derivatized [60]fullerene in a murine model of breast adenocarcinoma

[60]Fullerene is a highly versatile nanoparticle (NP) platform for drug delivery to sites of pathology owing to its small size and both ease and versatility of chemical functionalization, facilitating multisite drug conjugation, drug targeting, and modulation of its physicochemical properties. The prominent and well-characterized role of the enhanced permeation and retention (EPR) effect in facilitating NP delivery to tumors motivated us to explore vascular transport kinetics of a water-soluble [60]fullerene derivatives using intravital microscopy in an immune competent murine model of breast adenocarcinoma. Herein, we present a novel local and global image analysis of vascular transport kinetics at the level of individual tumor blood vessels on the micron scale and across whole images, respectively. Similar to larger nanomaterials, [60]fullerenes displayed rapid extravasation from tumor vasculature, distinct from that in normal microvasculature. Temporal heterogeneity in fullerene delivery to tumors was observed, demonstrating the issue of nonuniform delivery beyond spatial dimensions. Trends in local region analysis of fullerene biokinetics by fluorescence quantification were in agreement with global image analysis. Further analysis of intratumoral vascular clearance rates suggested a possible enhanced penetration and retention effect of the fullerene compared to a 70 kDa vascular tracer. Overall, this study demonstrates the feasibility of tracking and quantifying the delivery kinetics and intratumoral biodistribution of fullerene-based drug delivery platforms, consistent with the EPR effect on short timescales and passive transport to tumors

Dual enhancement in the radiosensitivity of prostate cancer through nanoparticles and chemotherapeutics

Abstract Background Radiotherapy (RT) is an essential component in the treatment regimens for many cancer patients. However, the dose escalation required to improve curative results is hindered due to the normal tissue toxicity that is induced. The introduction of radiosensitizers to RT treatment is an avenue that is currently being explored to overcome this issue. By introducing radiosensitizers into tumor sites, it is possible to preferentially enhance the local dose deposited. Gold nanoparticles (GNPs) are a potential candidate that have shown great promise in increasing the radiosensitivity of cancer cells through an enhancement in DNA damage. Furthermore, docetaxel (DTX) is a chemotherapeutic agent that arrests cells in the G2/M phase of the cell cycle, the phase most sensitive to radiation damage. We hypothesized that by incorporating DTX to GNP-enhanced radiotherapy treatment, we could further improve the radiosensitization experienced by cancer cells. To assess this strategy, we analyzed the radiotherapeutic effects on monolayer cell cultures in vitro, as well as on a mice prostate xenograft model in vivo while using clinically feasible concentrations for both GNPs and DTX. Results The introduction of DTX to GNP-enhanced radiotherapy further increased the radiotherapeutic effects experienced by cancer cells. A 38% increase in DNA double-strand breaks was observed with the combination of GNP/DTX vs GNP alone after a dose of 2 Gy was administered. In vivo results displayed significant reduction in tumor growth over a 30-day observation period with the treatment of GNP/DTX/RT when compared to GNP/RT after a single 5 Gy dose was given to mice. The treatment strategy also resulted in 100% mice survival, which was not observed for other treatment conditions. Conclusions Incorporating DTX to work in unison with GNPs and RT can increase the efficacy of RT treatment. Our study suggests that the treatment strategy could improve tumor control through local dose enhancement. As the concentrations used in this study are clinically feasible, there is potential for this strategy to be translated into clinical settings