A Versatile Carbonic Anhydrase IX Targeting Ligand-Functionalized Porous Silicon Nanoplatform for Dual Hypoxia Cancer Therapy and Imaging

Abstract

Hypoxia occurs in most solid tumors, and it has been shown to be an independent prognostic indicator of a poor clinical outcome for patients with various cancers. Therefore, constructing a nanosystem specifically targeting cancer cells under hypoxia conditions is a promising approach for cancer therapy. Herein, we develop a porous silicon (PSi)-based nanosystem for targeted cancer therapy. VD11-4-2, a novel inhibitor for carbonic anhydrase IX (CA IX), is anchored on PSi particles (VD-PSi). As CA IX is mainly expressed on the cancer cell membrane under hypoxia condition, this nanocomplex inherits a strong affinity toward hypoxic human breast adenocarcinoma (MCF-7) cells; thus, a better killing efficiency for the hypoxia-induced drug resistance cancer cell is observed. Furthermore, the release of doxorubicin (DOX) from VD-PSi showed pH dependence, which is possibly due to the hydrogen-bonding interaction between DOX and VD11-4-2. The fluorescence resonance energy transfer effect between DOX and VD11-4-2 is observed and applied for monitoring the DOX release intracellularly. Protein inhibition and binding assays showed that VD-PSi binds and inhibits CA IX. Overall, we developed a novel nanosystem inheriting several advantageous properties, which has great potential for targeted treatment of cancer cells under hypoxic conditions.

Tailoring Porous Silicon for Biomedical Applications: From Drug Delivery to Cancer Immunotherapy

“…Rabies virus glycoprotein (RVG) conjugation of PSi loaded with siRNA was investigated as potent brain targeting drug carrier, and the monitor of the emission from a Dy677 tag attached to the siRNA payload showed that the RVG–PSi construct delivered a substantial quantity of siRNA to the injured site and can reach up to threefold more accumulation in damaged brain tissue comparing to healthy brain (Figure b) . A carbonic anhydrase IX (CA IX, 3‐(cyclooctylamino)‐2,5,6‐trifluoro‐4‐((2‐hydroxyethyl)sulfonyl)benzenesulfonamide) targeting ligand‐functionalized PSi showed high affinity toward cancer cells under hypoxia condition, which presented potent application into cancer targeting . PSi surface biofunctionalization was developed for tumor associated endothelial cells and in macrophages targeting.…”

“…One common method is by conjugating fluorescence dye on the surface. Janoniene et al applied one fluorescence ligand, 3‐(cyclooctylamino)‐2,5,6‐trifluoro‐4‐((2‐hydroxyethyl)sulfonyl)benzenesulfonamide (VD11‐4‐2), into the surface modification of PSi. This is a fluorescence compound with maximum emission wavelength at 500 nm while the λ ex of DOX is 490 nm.…”

Advances in Porous Silicon–Based Nanomaterials for Diagnostic and Therapeutic Applications

“…pSi is an attractive material for the delivery of cytotoxic chemotherapeutics. There have been numerous reports on the delivery of chemotherapy drugs using pSiNPs with great efficacy . Recently, Santos has given an overview of chemotherapy using pSi; therefore, this review will focus on tackling anticancer drug resistance by means of combination therapy…”

Mucin 5B, carbonic anhydrase 9 and claudin 18 are potential theranostic markers of gallbladder carcinoma

“…24 Interestingly, different molecules have been developed to visualize hypoxic areas by the use of in-vivo imaging of CA9. [25][26][27][28] Here, we have demonstrated that CA9 is normally expressed at high and even levels in normal gallbladder epithelium, and was conserved at high levels in half of the GBC cases. Therefore, CA9 represents a promising candidate for theranostic strategies in GBC.…”

“…CA9 catalyses the reversible hydration of carbon dioxide; therefore, it has been studied as a potential target for cancer, as it is enriched in hypoxic niches of neoplastic tissues . Interestingly, different molecules have been developed to visualize hypoxic areas by the use of in‐vivo imaging of CA9 . Here, we have demonstrated that CA9 is normally expressed at high and even levels in normal gallbladder epithelium, and was conserved at high levels in half of the GBC cases.…”