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Cyclodextrin Complexation for Enhanced Stability and Non-invasive Pulmonary Delivery of Resveratrol—Applications in Non-small Cell Lung Cancer Treatment


Pulmonary drug delivery is a noninvasive therapeutic approach that offers many advantages including localized drug delivery and higher patient compliance. As with all formulations, the low aqueous solubility of a drug often poses a challenge in the formulation development. Thus, strategies such as cyclodextrin (CD) complexation have been utilized to overcome this challenge. Resveratrol (RES), a natural stilbene, has shown abundant anti-cancer properties. Due to many drawbacks of conventional chemotherapeutics, RES has been proposed as an emerging alternative with promising pharmacological effects. However, RES has limited therapeutic applications due to low water solubility, chemical stability, and bioavailability. This study was aimed at developing an inhalable therapy that would increase the aqueous solubility and stability of RES by complexation with sulfobutylether-β-cyclodextrin (SBECD). Phase solubility profiles indicated an optimal stoichiometric inclusion complex at 1:1 (SBECD:RES) ratio for formulation considerations. Physiochemical characterizations were performed to analyze CD-RES. Stability studies at pH 7.4 and in plasma indicated significant improvement in RES stability after complexation, with a much longer half-life. The mass median aerodynamic diameter (MMAD) of CD-RES was 2.6 ± 0.7 μm and fine particle fraction (FPF) of 83.4 ± 3.0% are suitable for pulmonary delivery and efficient deposition. Lung cancer was selected as the respiratory model disease, owing to its high relevance as the major cause of cancer deaths worldwide. Cell viability studies in 5 non-small-cell-lung-cancer (NSCLC) cell lines suggest CD-RES retained significant cytotoxic potential of RES. Taken together, CD-RES proves to be a promising inhalation treatment for NSCLC.

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Active pharmaceutical ingredient


Area under the curve




Complexation efficiency


Dimethyl sulfoxide


Differential scanning calorimetry


Fine particle fraction


Fourier transform infrared

IC50 :

50% inhibition concentration


Internal standard

Ks :

Apparent stability rate constant


Mass median aerodynamic diameter


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide


Next Generation Impactor ™


Nuclear magnetic resonance




Orthophosphoric acid


Phosphate-buffered saline






Small-cell lung cancer


Transmission electron microscopy


Scanning electron microscopy


Ultra-performance liquid chromatography


X-ray diffraction


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The authors would like to acknowledge the Imaging Facility of CUNY Advanced Science Research Center for instrument use, scientific and technical assistance.


This project was funded with the research funds to Vivek Gupta by the College of Pharmacy and Health Sciences, St. John’s University, Queens, NY. Xuechun Wang, Vineela Parvathaneni, and Dipti D Kanabar were supported with the teaching assistantships by St. John’s University. Snehal K Shukla was supported with the research assistantship from the National Institutes of Health (NIH) R15 grant (R15HL138606-01A1) to Vivek Gupta.

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Wang, X., Parvathaneni, V., Shukla, S.K. et al. Cyclodextrin Complexation for Enhanced Stability and Non-invasive Pulmonary Delivery of Resveratrol—Applications in Non-small Cell Lung Cancer Treatment. AAPS PharmSciTech 21, 183 (2020).

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  • resveratrol
  • sulfobutylether β-cyclodextrin
  • plasma stability
  • Next Generation Impactor™