Enhanced Stability and Bioactivity of Natural Anticancer Topoisomerase I Inhibitors through Cyclodextrin Complexation

Abstract

The use of cyclodextrins as drug nano-carrier systems for drug delivery is gaining importance in the pharmaceutical industry due to the interesting pharmacokinetic properties of the resulting inclusion complexes. In the present work, complexes of the anti-cancer alkaloids camptothecin and luotonin A have been prepared with β-cyclodextrin and hydroxypropyl-β-cyclodextrin. These cyclodextrin complexes were characterized by nuclear magnetic resonance spectroscopy (NMR). The variations in the 1H-NMR and 13C-NMR chemical shifts allowed to establish the inclusion modes of the compounds into the cyclodextrin cavities, which were supported by docking and molecular dynamics studies. The efficiency of the complexation was quantified by UV-Vis spectrophotometry and spectrofluorimetry, which showed that the protonation equilibria of camptothecin and luotonin A were drastically hampered upon formation of the inclusion complexes. The stabilization of camptothecin towards hydrolysis inside the cyclodextrin cavity was verified by the quantitation of the active lactone form by reverse phase liquid chromatography fluorimetric detection, both in basic conditions and in the presence of serum albumin. The antitumor activity of luotonin A and camptothecin complexes were studied in several cancer cell lines (breast, lung, hepatic carcinoma, ovarian carcinoma and human neuroblastoma) and an enhanced activity was found compared to the free alkaloids, particularly in the case of hydroxypropyl-β-cyclodextrin derivatives. This result shows that the cyclodextrin inclusion strategy has much potential towards reaching the goal of employing luotonin A or its analogues as stable analogues of camptothecin.

Aurisin A Complexed with 2,6-Di-O-methyl-β-cyclodextrin Enhances Aqueous Solubility, Thermal Stability, and Antiproliferative Activity against Lung Cancer Cells

“…The half-maximal inhibitory concentration (IC 50 ) values against the A549 and H1975 cells of the AA/DMβCD inclusion complex (17.14 ± 2.34 and 15.67 ± 1.33 μM) were significantly lower than those of the AA alone (32.77 ± 2.94 and 27.38 ± 3.17 μM) ( Figure 10 C). These findings are in good agreement with previous reports demonstrating that βCDs can distinctly enhance the anticancer activity of several hydrophobic compounds, such as camptothecin, luotonin A, resveratrol, mansonone G, curcumin, and scutellarein [ 23 , 43 , 44 , 45 , 46 ]. Thus, it was assumed that the enhanced antitumor effect of the AA/DMβCD inclusion complex was due to the improved water solubility and complex stability ( Figure 2 and Table 1 ).…”

Poly(amidoamine) Dendrimer/Camptothecin Complex: From Synthesis to In Vitro Cancer Cell Line Studies

“…It may imply interactions caused by an external electrostatic interaction, as well as hydrogen bonding between CPT and the PAMAM dendrimer. As a result, the NMR data support effective CPT internalization within the dendrimer structure rather than a physical mixture and are in accordance with previous literature data [ 23 , 29 ].…”

Exploring the Potential of Nanogels: From Drug Carriers to Radiopharmaceutical Agents

“…Drugs are loaded into CD-based nanogels through electrostatic and host-guest interactions, where the latter involves direct inclusion in the CD cavity or chemical modification with a strong guest like adamantane (Scheme 1). [140][141][142]136] This approach holds promise for enhancing drug delivery efficacy and overcoming solubility challenges in pharmaceutical applications.…”

“…Supramolecular chemistry of CDs comes to the rescue by integrating hydrophilic moieties into the nanogel's polymeric network, forming inclusion complexes for more efficient drug loading and controlled release, preventing the “burst effect.” Drugs are loaded into CD‐based nanogels through electrostatic and host–guest interactions, where the latter involves direct inclusion in the CD cavity or chemical modification with a strong guest like adamantane ( Scheme ). [ 140–142,136 ] This approach holds promise for enhancing drug delivery efficacy and overcoming solubility challenges in pharmaceutical applications.…”