Nanodiamonds as Possible Tools for Improved Management of Bladder Cancer and Bacterial Cystitis

Abstract

Nanodiamonds (NDs) are a class of carbon nanomaterials with sizes ranging from a few nm to micrometres. Due to their excellent physical, chemical and optical properties, they have recently attracted much attention in biomedicine. In addition, their exceptional biocompatibility and the possibility of precise surface functionalisation offer promising opportunities for biological applications such as cell labelling and imaging, as well as targeted drug delivery. However, using NDs for selective targeting of desired biomolecules within a complex biological system remains challenging. Urinary bladder cancer and bacterial cystitis are major diseases of the bladder with high incidence and poor treatment options. In this review, we present: (i) the synthesis, properties and functionalisation of NDs; (ii) recent advances in the study of various NDs used for better treatment of bladder cancer and (iii) bacterial cystitis; and (iv) the use of NDs in theranostics of these diseases.

Keywords: bacterial cystitis; bladder cancer; functionalisation; nanodiamonds; urinary bladder.

Figure 1

Basic formation of uniform surface constituents on NDs by carboxylation (a), hydroxylation (b), hydrogenation (c) and amination (d). The actual surface constituents and their relative abundance are determined by the production methods and subsequent purification steps. The illustration was created by the authors using the BioRender app.

Figure 2

Useful functionalisation of NDs by non-covalent binding of DNA (a), peptide (b), lectin (c), drugs such as doxorubicin (DOX; (d)) and retinoic acid (RA; (e)) [6,21,48]. The illustration was created by the authors using the BioRender app.

Figure 3

Endocytosis and intracellular pathway of retinoic acid (RA) conjugated to ND. (a) After endosome formation in the cell, the crucial step is the release of RA from the endosome and its binding to the cellular retinoic acid-binding protein (CRABP). CRABP transports RA into the nucleus, where it can form large protein complexes consisting of co-activators and the retinoic acid receptor (RAR) and retinoid X receptor (RXR), activating RA response elements (RARE). (b,c) Internalisation assay performed with two human cell lines: non-invasive papillary urothelial cancer cells RT4 (b) and invasive urothelial cancer cells T24 (c). For both cell lines, DNDs were added to the culture medium at a concentration of 11 µg/mL for 24 h and cells were prepared for transmission electron microscopy. DNDs were observed in endocytotic compartments (black arrows; (b,c)) and in multilamellar bodies (white arrow; c). A detailed analysis of the endocytosis of DNDs is published in [5]. Scale bars: 500 nm. The illustration was created by the authors using the BioRender app and our own TEM images.

Figure 4

Possible mechanism to prevent UPEC from attaching to urothelial cells. (a) The apical plasma membrane of the umbrella cell has transmembrane proteins uroplakin Ia (UPIa) with four transmembrane domains and mannose units to which UPEC attach before entering the cell. (b) NDs conjugated with mannose units could bind to UPEC, occupying the binding sites and thus preventing their attachment to umbrella cells. The illustration was created by the authors using the BioRender app.

Figure 5

Possible mechanism for elimination of the intracellular bacterial community (IBC) of UPEC in superficial urothelial umbrella cells. (a) The apical plasma membrane of the umbrella cell has transmembrane proteins uroplakin Ia (UPIa) with four transmembrane domains and mannose units to which UPEC attach before entering the cell and forming IBC within the cell. (b) Antibiotics cannot penetrate the apical plasma membrane of the umbrella cell and therefore cannot reach and eliminate UPEC within the IBC. (c) Antibiotics bound to NDs can penetrate the apical plasma membrane of the umbrella cell. (d) Once inside the cell, the antibiotics reach the IBC, dissociate from the NDs and eliminate the intracellular reservoir of UPEC within the IBC. The illustration was created by the authors using the BioRender app.