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

Abstract

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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Abbreviations

ACN:

Acetonitrile

API:

Active pharmaceutical ingredient

AUC:

Area under the curve

CD:

Cyclodextrin

CE:

Complexation efficiency

DMSO:

Dimethyl sulfoxide

DSC:

Differential scanning calorimetry

FPF:

Fine particle fraction

FTIR:

Fourier transform infrared

IC50 :

50% inhibition concentration

IS:

Internal standard

Ks :

Apparent stability rate constant

MMAD:

Mass median aerodynamic diameter

MTT:

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

NGI:

Next Generation Impactor ™

NMR:

Nuclear magnetic resonance

NSCLC:

Non-small-cell-lung-cancer

OPA:

Orthophosphoric acid

PBS:

Phosphate-buffered saline

RES:

Resveratrol

SBECD:

Sulfobutylether-β-cyclodextrin

SCLC:

Small-cell lung cancer

TEM:

Transmission electron microscopy

SEM:

Scanning electron microscopy

UPLC:

Ultra-performance liquid chromatography

XRD:

X-ray diffraction

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Acknowledgments

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

Funding

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). https://doi.org/10.1208/s12249-020-01724-x

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KEY WORDS

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