pH-Responsive Drug Delivery Nanoplatforms as Smart Carriers of Unsymmetrical Bisacridines for Targeted Cancer Therapy

Abstract

Selective therapy and controlled drug release at an intracellular level remain key challenges for effective cancer treatment. Here, we employed folic acid (FA) as a self-navigating molecule in nanoconjugates containing quantum dots (QDs) and β-cyclodextrin (β-CD) for the delivery of antitumor unsymmetrical bisacridine compound (C-2028) to lung and prostate cancers as well as normal cells. The bisacridine derivative can form the inclusion complex with β-cyclodextrin molecule, due to the presence of a planar fragment in its structure. The stability of such a complex is pH-dependent. The drug release profile at different pH values and the mechanism of C-2028 release from QDs-β-CD-FA nanoconjugates were investigated. Next, the intracellular fate of compounds and their influence on lysosomal content in the cells were also studied. Confocal Laser Scanning Microscopy studies proved that all investigated compounds were delivered to acidic organelles, the pH of which promoted an increased release of C-2028 from its nanoconjugates. Since the pH in normal cells is higher than in cancer cells, the release of C-2028 from its nanoconjugates is decreased in these cells. Additionally, we obtained the concentration profiles of C-2028 in the selected cells treated with unbound C-2028 or nanoconjugate by the HPLC analysis.

Cellular Effects of Selected Unsymmetrical Bisacridines on the Multicellular Tumor Spheroids of HCT116 Colon and A549 Lung Cancer Cells in Comparison to Monolayer Cultures

“…It has been observed lately that the localization of UAs in cells is pH-dependent, and an increased concentration of these compounds in organelles with low pH has also been detected [25,51]. This-along with the fact that pH strongly influences UA protonation states, self-association ratio, and solubility [52]-may provide some insight into why some of these compounds exhibit even more promising results in 3D spheroids, which are characterized by a specific pH gradient that is similar to that observed in vivo.…”

Recent Advances in Targeted Drug Delivery Strategy for Enhancing Oncotherapy

“…Folic acid is a member of the B vitamin family, whose receptors are overexpressed on tumor cells, and folic acid can be used as a ligand to bind with high affinity to the receptor on the tumor for targeted delivery to the tumor site (see Figure 8 ) [ 121 ]. Joanna et al used β -cyclodextrin-modified quantum dots as a carrier and folic acid as a targeted ligand for drug delivery to tumor tissue, synthesizing the nanocomplex QDs- β -CD-FA; the addition of FA significantly enhanced the endocytosis of nanoparticles by tumor cells [ 122 ].…”

The interactions of monomeric acridines and unsymmetrical bisacridines (UAs) with DNA duplexes: an insight provided by NMR and MD studies

“…Time-dependent determination of UA concentration after prolonged incubation reveals either increased, decreased or constant concentration of UAs in cells 3 . Moreover, a pH-dependent localization of UAs in the cell has been observed, as UA concentration was increased in organelles characterized by low pH, such as lysosomes and endosomes 3 , 5 .…”