Complementary Nucleobase Interactions Drive Co-Assembly of Drugs and Nanocarriers for Selective Cancer Chemotherapy

Abstract

A new concept in cooperative adenine–uracil (A–U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes was successfully demonstrated by invoking the co-assembly of water soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system for the achievement of targeted, more efficient cancer chemotherapy. Due to A–U base pairing between BU-PEG and A-R6G, BU-PEG has high tendency to interact with A-R6G, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution. The resulting nanogels exhibit a number of unique physical properties, including extremely high A-R6G-loading capacity, well-controlled, pH-triggered A-R6G release behavior, and excellent structural stability in biological media. Importantly, a series of in vitro cellular experiments clearly demonstrated that A-R6G/BU-PEG nanogels improved the selective uptake of A-R6G by cancer cells via endocytosis and promoted the intracellular release of A-R6G to subsequently induce apoptotic cell death, while control rhodamine/BU-PEG nanogels did not exert selective toxicity in cancer or normal cell lines. Overall, these results indicate that cooperative A–U base pairing within nanogels is a critical factor that improves selective drug uptake and effectively promotes apoptotic programmed cell death in cancer cells.

A CO2-Responsive Imidazole-Functionalized Fluorescent Material Mediates Cancer Chemotherapy

“…In order to determine the mechanisms by which CO 2 -treated I-R6G mediates potent cytotoxicity in HeLa cells, a double staining flow cytometric assay was employed to estimate the percentages of live, apoptotic and necrotic cells after incubation of NIH/3T3 or HeLa cells with pristine or CO 2 -treated I-R6G for different periods of time. As indicated in Figure 5 e–l and Figure S15 , double Ghost Dye™ Red 780 (GDR-780) and Brilliant Violet-421™ Annexin V (BV421 Annexin V) staining were employed to quantify necrotic cells (BV421 Annexin V negative and GDR-780 positive; upper left quadrant; Q1), late apoptotic cells (BV421 Annexin V positive and GDR-780 positive; upper right quadrant; Q2), early apoptotic cells (BV421 Annexin V positive and GDR-780 negative; lower right quadrant; Q3) and live cells (BV421 Annexin V negative and GDR-780 negative; lower left quadrant; Q4) [ 38 , 39 , 68 , 69 ]. Up to 99 and 98% of NIH/3T3 and HeLa cells remained viable after culture with pristine I-R6G for 24 h, respectively, proving once again that pristine I-R6G does not exert any cytotoxic effects in either cell line ( Figure S15 ).…”

“…Thus, R6G may be modified to confer multiple biofunctional properties and potentially generate effective anti-cancer drugs with potent cytotoxicity, and the fluorescent distribution of these drugs can be tracked in living cells. However, despite this potential, several challenges have limited the development of R6G for chemotherapy, such as its tendency to form large aggregates in aqueous media [ 37 ], lack of structural stability in biological environments and insufficient selective internalisation by cancer cells [ 38 , 39 ]. As a potential strategy to combat these multifaceted challenges, we reasonably speculated that the combination of R6G with a CO 2 -responsive imidazole group may potentially allow the development of intelligent anticancer drug systems with improved structural stability and potent anticancer cytotoxicity, and may also represent a strategy to enhance the overall efficacy and safety profile of medicines used for chemotherapy.…”

“…Our recent studies proved that the introduction of adenine moieties remarkably altered the amphiphilicity and fluorescence behaviour of R6G and promoted the co-assembly of uracil-functionalised supramolecular polymers into stable spherical nanogels. The resulting enhanced structural stability and selective delivery of the adenine-functionalised R6G drug into cancer cells eventually promoted rapid intracellular drug release and massive apoptotic cell death [ 38 , 39 ]. Based on these previous findings, we further extended our efforts to develop CO 2 -responsive functional anticancer drugs (I-R6G) by introducing imidazole groups into R6G, with the objectives of endowing CO 2 responsiveness to R6G in an aqueous environment and also manipulating its structural stability and physical characteristics.…”

Supramolecular Systems for Gene and Drug Delivery

“…Several biomaterial-based supramolecular systems (cyclodextrins [ 1 ], calixarenes [ 2 , 3 ], polymers [ 4 ], carbon nanotubes [ 5 ], nanoparticles [ 6 , 7 ], liposomes [ 3 , 8 ], nanogels [ 9 ], and nanocomplexes [ 10 ], among others) have been widely used for biomedical applications, such as gene and drug delivery. Numerous researchers have developed novel supramolecular systems for enhancing their biocompatibility and pharmacological activity, thus increasing their therapeutic properties.…”

“…F. Bintang Ilhami et al [ 9 ] developed a new concept in cooperative adenine–uracil (A-U) hydrogen bonding interactions between anticancer drugs and nanocarrier complexes, which was successfully demonstrated by invoking the co-assembly of water-soluble, uracil end-capped polyethylene glycol polymer (BU-PEG) upon association with the hydrophobic drug adenine-modified rhodamine (A-R6G). This concept holds promise as a smart and versatile drug delivery system, which leads to the formation of self-assembled A-R6G/BU-PEG nanogels in aqueous solution, for the achievement of targeted, more efficient cancer chemotherapy.…”