Bioconjugation of Supramolecular Metallacages to Integrin Ligands for Targeted Delivery of Cisplatin

Abstract

Cisplatin occupies a crucial role in the treatment of various malignant tumours. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity towards healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that encapsulated drug is less accumulated in these organs compared to the 'free' one.

Highly luminescent metallacages featuring bispyridyl ligands functionalised with BODIPY for imaging in cancer cells

“…[10] Moreover, reduced toxicity of cisplatin encapsulated in integrin-targeted metallacages was also demonstrated in healthy tissues ex vivo. [10] While the Pd2L4 cages are very promising for cisplatin delivery, their mechanism of cancer cell uptake is still not fully understood; this prevents their optimisation as targeted drug vectors. In order to 3 study the cages intracellular accumulation and sub-cellular localisation, fluorescence microscopy is the preferred technique, allowing analysis with intact cells while avoiding complex cell fractionation steps which may lead to reduced analyte recovery, and lack of reproducibility.…”

“…All the ligand precursors and cages were characterised by various methods, including 1 H, 13 Figure 1 and show that, upon cage formation, significant downfield chemical shifts of protons peaks Ha and Hb, indicative of coordination to the Pd(II) ions, can be observed in accordance with previously reported studies. [8,10,11] Furthermore, the ligands and cages were studied for their emission properties, and the respective quantum yields (Table 1) calculated as described in the experimental section. Of note, at variance with previously reported metallacages exo-functionalised with different fluorophores, [13] the BODIPY-cages maintained excellent quantum yield values.…”

“…We have previously demonstrated the encapsulation of cisplatin within Pd2L4 metallacages via 1 H NMR spectroscopy in DMF-d7. [10,23] Similarly, metallacages C1.BF4 and C1.NO3 were dissolved in DMF-d7 and the respective 1 H NMR spectra were recorded. Afterward, two equiv.…”

“…[9] Thus, we selected peptidic ligands for targeting of integrins overexpressed in cancer cells. [10] The results showed that cisplatin encapsulated in the targeted cages had a two-fold increase in cytotoxic potency in melanoma cells after 24 h incubation. [10] Moreover, reduced toxicity of cisplatin encapsulated in integrin-targeted metallacages was also demonstrated in healthy tissues ex vivo.…”

“…[10] The results showed that cisplatin encapsulated in the targeted cages had a two-fold increase in cytotoxic potency in melanoma cells after 24 h incubation. [10] Moreover, reduced toxicity of cisplatin encapsulated in integrin-targeted metallacages was also demonstrated in healthy tissues ex vivo. [10] While the Pd2L4 cages are very promising for cisplatin delivery, their mechanism of cancer cell uptake is still not fully understood; this prevents their optimisation as targeted drug vectors.…”