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
References
Abdelaziz HM, Gaber M, Abd-Elwakil MM, Mabrouk MT, Elgohary MM, Kamel NM, et al. Inhalable particulate drug delivery systems for lung cancer therapy: nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release. 2018;269:374–92.
Sorino C, Negri S, Spanevello A, Visca D, Scichilone N. Inhalation therapy devices for the treatment of obstructive lung diseases: the history of inhalers towards the ideal inhaler. Eur J Intern Med. 2020;S0953620520300686.
Wang H, Wu L, Sun X. Intratracheal delivery of nano- and microparticles and hyperpolarized gases. Chest. 2019;S0012369219344484.
Anderson CF, Grimmett ME, Domalewski CJ, Cui H. Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases. WIREs Nanomedicine Nanobiotechnology [Internet]. 2020 Jan [cited 2020 Apr 8];12(1). Available from: https://doi.org/10.1002/wnan.1586
Alhajj N, Chee CF, Wong TW, Rahman NA, Abu Kasim NH, Colombo P. Lung cancer: active therapeutic targeting and inhalational nanoproduct design. Expert Opin Drug Deliv. 2018;15(12):1223–47.
Borghardt JM, Kloft C, Sharma A. Inhaled therapy in respiratory disease: the complex interplay of pulmonary kinetic processes. Can Respir J. 2018;2018:1–11.
Ngan CL, Asmawi AA. Lipid-based pulmonary delivery system: a review and future considerations of formulation strategies and limitations. Drug Deliv Transl Res. 2018;8(5):1527–44.
Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I: physiological factors affecting therapeutic effectiveness of aerosolized medications: physiological factors affecting the effectiveness of inhaled drugs. Br J Clin Pharmacol. 2003;56(6):588–99.
Elsayed I, AbouGhaly MHH. Inhalable nanocomposite microparticles: preparation, characterization and factors affecting formulation. Expert Opin Drug Deliv. 2016;13(2):207–22.
Olsson B, Bondesson E, Borgström L, Edsbäcker S, Eirefelt S, Ekelund K, et al. Pulmonary drug metabolism, clearance, and absorption. In: Smyth HDC, Hickey AJ, editors. Controlled pulmonary drug delivery [Internet]. New York, NY: Springer New York; 2011 [cited 2020 Apr 3]. p. 21–50. Available from: https://doi.org/10.1007/978-1-4419-9745-6_2
Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012;2012:1–10.
Wankar J, Kotla NG, Gera S, Rasala S, Pandit A, Rochev YA. Recent advances in host–guest self-assembled cyclodextrin carriers: implications for responsive drug delivery and biomedical engineering. Adv Funct Mater. 2020;5:1909049.
Kurkov SV, Loftsson T. Cyclodextrins. Int J Pharm. 2013 Aug;453(1):167–80.
Vaidya B, Shukla SK, Kolluru S, Huen M, Mulla N, Mehra N, et al. Nintedanib-cyclodextrin complex to improve bio-activity and intestinal permeability. Carbohydr Polym. 2019;204:68–77.
Zhang Y, Cui Y-L, Gao L-N, Jiang H-L. Effects of β-cyclodextrin on the intestinal absorption of berberine hydrochloride, a P-glycoprotein substrate. Int J Biol Macromol. 2013;59:363–71.
Zhang Y, Meng F-C, Cui Y-L, Song Y-F. Enhancing effect of hydroxypropyl-β-cyclodextrin on the intestinal absorption process of genipin. J Agric Food Chem. 2011;59(20):10919–26.
Zhang T, Zhu L, Li M, Hu Y, Zhang E, Jiang Q, et al. Inhalable andrographolide-β-cyclodextrin inclusion complexes for treatment of Staphylococcus aureus pneumonia by regulating immune responses. Mol Pharm. 2017;14(5):1718–25.
Mohtar N, Taylor KMG, Sheikh K, Somavarapu S. Design and development of dry powder sulfobutylether-β-cyclodextrin complex for pulmonary delivery of fisetin. Eur J Pharm Biopharm. 2017;113:1–10.
Frischholz S, Berberich O, Böck T, Meffert RH, Blunk T. Resveratrol counteracts IL-1β-mediated impairment of extracellular matrix deposition in 3D articular chondrocyte constructs. J Tissue Eng Regen Med. 2020 Mar 17;term.3031.
Xing C, Wang Y, Dai X, Yang F, Luo J, Liu P, et al. The protective effects of resveratrol on antioxidant function and the mRNA expression of inflammatory cytokines in the ovaries of hens with fatty liver hemorrhagic syndrome. Poult Sci. 2020;99(2):1019–27.
Wright C, Krishnan V, Iyer A, Yakisich JS, Azad N. Anti-tumorigenic effects of resveratrol in lung cancer cells through modulation of c-FLIP. Curr Cancer Drug Targets. 2017;9:17(7).
Jeong H, Phan AiNH, Choi J-W. Anti-cancer effects of polyphenolic compounds in epidermal growth factor receptor tyrosine kinase inhibitor-resistant non-small cell lung cancer. Pharmacogn Mag. 2017;13(52):595.
Wang J, Li J, Cao N, Li Z, Han J, Li L. Resveratrol, an activator of SIRT1, induces protective autophagy in non-small-cell lung cancer via inhibiting Akt/mTOR and activating p38-MAPK. OncoTargets Ther. 2018;11:7777–86.
Meng X, Maliakal P, Lu H, Lee M-J, Yang CS. Urinary and plasma levels of resveratrol and quercetin in humans, mice, and rats after ingestion of pure compounds and grape juice. J Agric Food Chem. 2004;52(4):935–42.
Walle T, Hsieh F, DeLegge MH, Oatis JE, Walle UK. High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos. 2004;32(12):1377–82.
Gescher AJ, Steward WP. Relationship between mechanisms, bioavailibility, and preclinical chemopreventive efficacy of resveratrol: a conundrum. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2003;12(10):953–7.
Sergides C, Chirilă M, Silvestro L, Pitta D, Pittas A. Bioavailability and safety study of resveratrol 500 mg tablets in healthy male and female volunteers. Exp Ther Med. 2016;11(1):164–70.
Almeida L, Vaz-da-Silva M, Falcão A, Soares E, Costa R, Loureiro AI, et al. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. Mol Nutr Food Res. 2009;53(S1):S7–15.
Spogli R, Bastianini M, Ragonese F, Iannitti R, Monarca L, Bastioli F, et al. Solid dispersion of resveratrol supported on magnesium dihydroxide (Resv@MDH) microparticles improves oral bioavailability. Nutrients. 2018;10(12):1925.
Seljak KB, Berginc K, Trontelj J, Zvonar A, Kristl A, Gašperlin M. A self-microemulsifying drug delivery system to overcome intestinal resveratrol toxicity and presystemic metabolism. J Pharm Sci. 2014;103(11):3491–500.
Amri A, Chaumeil JC, Sfar S, Charrueau C. Administration of resveratrol: what formulation solutions to bioavailability limitations? J Control Release. 2012;158(2):182–93.
Muller AG, Sarker SD, Saleem IY, Hutcheon GA. Delivery of natural phenolic compounds for the potential treatment of lung cancer. DARU J Pharm Sci. 2019;27(1):433–49.
Venuti V, Cannavà C, Cristiano MC, Fresta M, Majolino D, Paolino D, et al. A characterization study of resveratrol/sulfobutyl ether-β-cyclodextrin inclusion complex and in vitro anticancer activity. Colloids Surf B: Biointerfaces. 2014;115:22–8.
Torres V, Hamdi M, Millán de la Blanca M, Urrego R, Echeverri J, López-Herrera A, et al. Resveratrol-cyclodextrin complex affects the expression of genes associated with lipid metabolism in bovine in vitro produced embryos. Reprod Domest Anim 2018;53(4):850–858.
Cheng JG, Tian BR, Huang Q, Ge HR, Wang ZZ. Resveratrol functionalized carboxymethyl- β-cyclodextrin: synthesis, characterization, and photostability. J Chemother. 2018;2018:1–7.
Lucas-Abellán C, Fortea I, López-Nicolás JM, Núñez-Delicado E. Cyclodextrins as resveratrol carrier system. Food Chem. 2007;104(1):39–44.
Cancer Facts & Figures 2020 | American Cancer Society [Internet]. [cited 2020 Mar 17]. Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html
Wattanathamsan O, Hayakawa Y, Pongrakhananon V. Molecular mechanisms of natural compounds in cell death induction and sensitization to chemotherapeutic drugs in lung cancer. Phytother Res. 2019;33(10):2531–47.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.
Robinson K, Mock C, Liang D. Pre-formulation studies of resveratrol. Drug Dev Ind Pharm. 2015;41(9):1464–9.
Shukla SK, Kadry H, Bhatt JA, Elbatanony R, Ahsan F, Gupta V. Statistical optimization and validation of a novel ultra-performance liquid chromatography method for estimation of nintedanib in rat and human plasma. Bioanalysis. 2020;12(3):159–74.
Vaidya B, Parvathaneni V, Kulkarni NS, Shukla SK, Damon JK, Sarode A, et al. Cyclodextrin modified erlotinib loaded PLGA nanoparticles for improved therapeutic efficacy against non-small cell lung cancer. Int J Biol Macromol. 2019;122:338–47.
Higuchi T. A phase solubility technique. Adv Anal Chem Instrum. 1965;4:117–211.
Loftsson T, Brewster ME. Cyclodextrins as functional excipients: methods to enhance complexation efficiency. J Pharm Sci. 2012;101(9):3019–32.
Lengauer T, Rarey M. Computational methods for biomolecular docking. Curr Opin Struct Biol. 1996;6(3):402–6.
Vaidya B, Kulkarni NS, Shukla SK, Parvathaneni V, Chauhan G, Damon JK, et al. Development of inhalable quinacrine loaded bovine serum albumin modified cationic nanoparticles: repurposing quinacrine for lung cancer therapeutics. Int J Pharm. 2020;577:118995.
Shukla SK, Kulkarni NS, Farrales P, Kanabar DD, Parvathaneni V, Kunda NK, et al. Sorafenib loaded inhalable polymeric nanocarriers against non-small cell lung cancer. Pharm Res. 2020;37(3):67.
Lu Z, Chen R, Fu R, Xiong J, Hu Y. Cytotoxicity and inhibition of lipid peroxidation activity of resveratrol/cyclodextrin inclusion complexes. J Incl Phenom Macrocycl Chem. 2012;73(1–4):313–20.
Duarte A, Martinho A, Luís Â, Figueiras A, Oleastro M, Domingues FC, et al. Resveratrol encapsulation with methyl-β-cyclodextrin for antibacterial and antioxidant delivery applications. LWT Food Sci Technol. 2015;63(2):1254–60.
Das SK, Kahali N, Bose A, Khanam J. Physicochemical characterization and in vitro dissolution performance of ibuprofen-Captisol® (sulfobutylether sodium salt of β-CD) inclusion complexes. J Mol Liq. 2018 Jul 1;261:239–49.
Ansari KA, Vavia PR, Trotta F, Cavalli R. Cyclodextrin-based Nanosponges for delivery of resveratrol: in vitro characterisation, stability. Cytotoxicity and Permeation Study AAPS PharmSciTech. 2011;12(1):279–86.
Parvathaneni V, Kulkarni NS, Shukla SK, Farrales PT, Kunda NK, Muth A, et al. Systematic development and optimization of inhalable Pirfenidone liposomes for non-small cell lung cancer treatment. Pharmaceutics. 2020;12(3):206.
Pagliaro B, Santolamazza C, Simonelli F, Rubattu S. Phytochemical compounds and protection from cardiovascular diseases: a state of the art. Biomed Res Int. 2015;2015:918069.
Tiwari G, Tiwari R, Rai AK. Cyclodextrins in delivery systems: applications. J Pharm Bioallied Sci. 2010;2(2):72–9.
Arima H, Miyaji T, Irie T, Hirayama F, Uekama K. Enhancing effect of hydroxypropyl-beta-cyclodextrin on cutaneous penetration and activation of ethyl 4-biphenylyl acetate in hairless mouse skin. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 1998;6(1):53–9.
Ueda H, Ou D, Endo T, Nagase H, Tomono K, Nagai T. Evaluation of a sulfobutyl ether β-cyclodextrin as a solubilizing/stabilizing agent for several drugs. Drug Dev Ind Pharm. 1998;24(9):863–7.
Zhong Q, Bielski ER, Rodrigues LS, Brown MR, Reineke JJ, da Rocha SRP. Conjugation to poly(amidoamine) dendrimers and pulmonary delivery reduce cardiac accumulation and enhance antitumor activity of doxorubicin in lung metastasis. Mol Pharm. 2016;13(7):2363–75.
Ren Z, Xu Y, Lu Z, Wang Z, Chen C, Guo Y, et al. Construction of a water-soluble and photostable rubropunctatin/β-cyclodextrin drug carrier. RSC Adv. 2019;9(20):11396–405.
Wang S, Li F, Quan E, Dong D, Wu B. Efflux transport characterization of resveratrol glucuronides in UDP-glucuronosyltransferase 1A1 transfected hela cells: application of a cellular pharmacokinetic model to decipher the contribution of multidrug resistance-associated protein 4. Drug Metab Dispos. 2016;44(4):485–8.
Kulkarni NS, Parvathaneni V, Shukla SK, Barasa L, Perron JC, Yoganathan S, et al. Tyrosine kinase inhibitor conjugated quantum dots for non-small cell lung cancer (NSCLC) treatment. Eur J Pharm Sci. 2019;133:145–59.
Shukla SK, Kulkarni NS, Chan A, Parvathaneni V, Farrales P, Muth A, et al. Metformin-encapsulated liposome delivery system: an effective treatment approach against breast cancer. Pharmaceutics. 2019;11(11):559.
Borkowska M, Siek M, Kolygina DV, Sobolev YI, Lach S, Kumar S, et al. Targeted crystallization of mixed-charge nanoparticles in lysosomes induces selective death of cancer cells. Nat Nanotechnol [Internet]. 2020 Mar 16 [cited 2020 Mar 21]; Available from: http://www.nature.com/articles/s41565-020-0643-3
Gupta V, Davis M, Hope-Weeks LJ, Ahsan F. PLGA microparticles encapsulating prostaglandin E1-hydroxypropyl-β-cyclodextrin (PGE1-HPβCD) complex for the treatment of pulmonary arterial hypertension (PAH). Pharm Res. 2011;28(7):1733–49.
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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DOI: https://doi.org/10.1208/s12249-020-01724-x