Topical chemotherapy approaches are relevant for certain skin cancer treatments. This study observes that cabazitaxel (CTX), a broad-spectrum second-generation taxane cytotoxic agent, can be dissolved in α-tocopherol at high concentrations exceeding 100 mg mL-1 . 2D nuclear magnetic resonance (NMR) analysis and molecular dynamics (MD) are used to study this phenomenon. The addition of 30% dimethyl sulfoxide (DMSO) to the α-tocopherol/CTX solution improves its working viscosity and enhances CTX permeation through human skin in vitro (over 5 µg cm-2 within 24 h), while no detectable drug permeates when CTX is dissolved in α-tocopherol alone. In a transepidermal water loss assay, the barrier impairment induced by CTX in 30% DMSO in α-tocopherol, but not in pure DMSO, is reversible 8 h after the formulation removal from the skin surface. Antitumor efficacy of the topical CTX formulation is evaluated in nude mice bearing A431 human squamous carcinoma skin cancer xenografts. With topical application of concentrated CTX solutions (75 mg mL-1 ), tumor growth is significantly suppressed compared to lower concentration groups (0, 25, or 50 mg mL-1 CTX). Taken together, these findings show that topical delivery of CTX using a DMSO and α-tocopherol solvent warrants further study as a treatment for skin malignancies.

Department of Biomedical Engineering State University of New York at Buffalo Buffalo NY 14260 USA

Department of Chemistry State University of New York at Buffalo Buffalo NY 14260 USA

School of Chemical Engineering and Technology Key Laboratory of Systems Bioengineering State Key Laboratory of Chemical Engineering Tianjin University Tianjin 300350 P R China

Skin Barrier Research Group Faculty of Pharmacy Charles University Akademika Heyrovského 1203 Hradec Králové 50005 Czech Republic

Zobrazit více v PubMed

Rembielak A., Ajithkumar T., Clin. Oncol. 2019, 31, 735. PubMed

Ciążyńska M., Kamińska‐Winciorek G., Lange D., Lewandowski B., Reich A., Sławińska M., Pabianek M., Szczepaniak K., Hankiewicz A., Ułańska M., Morawiec J., Błasińska‐Morawiec M., Morawiec Z., Piekarski J., Nejc D., Brodowski R., Zaryczańska A., Sobjanek M., Nowicki R. J., Owczarek W., Słowińska M., Wróbel K., Bieniek A., Woźniacka A., Skibińska M., Narbutt J., Niemczyk W., Ciążyński K., Lesiak A., Sci. Rep. 2021, 11, 4337. PubMed PMC

Simões M. C. F., Sousa J. J. S., Pais A., Cancer Lett. 2015, 357, 8. PubMed

Pfeifer G. P., Besaratinia A., Photochem. Photobiol. Sci. 2012, 11, 90. PubMed PMC

Khan M. A., Pandit J., Sultana Y., Sultana S., Ali A., Aqil M., Chauhan M., Drug Deliv. 2015, 22, 795. PubMed

a) Gupta A. K., Cutis 2002, 70, 30; PubMed

b) Jorizzo J., Stewart D., Bucko A., Davis S. A., Espy P., Hino P., Rodriguez D., Savin R., Stough D., Furst K., Connolly M., Levy S., Cutis 2002, 70, 335; PubMed

c) Levy S., Furst K., Chern W., Clin. Ther. 2001, 23, 901; PubMed

d) Alexandridis P., Holzwarth J. F., Hatton T. A., Macromolecules 1994, 27, 2414;

e) Loven K., Stein L., Furst K., Levy S., Clin. Ther. 2002, 24, 990; PubMed

f) Robins P., Gupta A. K., Cutis 2002, 70, 4. PubMed

Crown J., O'Leary M., Lancet 2000, 355, 1176. PubMed

Jordan M. A., Wilson L., Nat. Rev. Cancer 2004, 4, 253. PubMed

a) Sun B., Lovell J. F., Zhang Y., Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2023, 15, e1854; PubMed

b) Sun B., Straubinger R. M., Lovell J. F., Nano Res. 2018, 11, 5193.

de Bono J. S., Oudard S., Ozguroglu M., Hansen S., Machiels J. P., Kocak I., Gravis G., Bodrogi I., Mackenzie M. J., Shen L., Roessner M., Gupta S., Sartor A. O., Lancet 2010, 376, 1147. PubMed

a) Han X., Chen D., Sun J., Zhou J., Li D., Gong F., Shen Y., J. Biomater. Sci., Polym. Ed. 2016, 27, 626; PubMed

b) Zhuang B., Du L., Xu H., Xu X., Wang C., Fan Y., Cong M., Yin J., Li H., Guan H., Int. J. Pharm. 2016, 499, 146; PubMed

c) Mahdaviani P., Bahadorikhalili S., Navaei‐Nigjeh M., Vafaei S. Y., Esfandyari‐Manesh M., Abdolghaffari A. H., Daman Z., Atyabi F., Ghahremani M. H., Amini M., Lavasanifar A., Dinarvand R., Mater. Sci. Eng., C 2017, 80, 301; PubMed

d) He B., Tan T., Wang H., Hu H., Wang Z., Wang J., Li J., Sun K., Zhang Z., Li Y., Adv. Funct. Mater. 2018, 28, 1705622;

e) Zhong T., He B., Cao H. Q., Tan T., Hu H. Y., Li Y. P., Zhang Z. W., Acta Pharmacol. Sin. 2017, 38, 924; PubMed PMC

f) Aydin O., Youssef I., Yuksel Durmaz Y., Tiruchinapally G., ElSayed M. E., Mol. Pharm. 2016, 13, 1413; PubMed

g) Sun B., Chitgupi U., Li C., Federizon J., Zhang C., Ruszaj D. M., Razi A., Ortega J., Neelamegham S., Zhang Y., Adv. Ther. 2020, 3, 1900161;

h) Sun B., Jing H., Mabrouk M. T., Zhang Y., Jin H., Lovell J. F., Pharm. Dev. Technol. 2020, 25, 1281; PubMed PMC

i) Zhang Y., Song W., Geng J., Chitgupi U., Unsal H., Federizon J., Rzayev J., Sukumaran D. K., Alexandridis P., Lovell J. F., Nat. Commun. 2016, 7, 11649; PubMed PMC

j) Barve A., Jain A., Liu H., Zhao Z., Cheng K., Acta Biomater. 2020, 113, 501. PubMed PMC

a) Kommineni N., Mahira S., Domb A. J., Khan W., Pharmaceutics 2019, 11, 141; PubMed PMC

b) Zeng Y.‐Y., Zeng Y.‐J., Zhang N.‐N., Li C.‐X., Xie T., Zeng Z.‐W., Molecules 2019, 24, 1697; PubMed PMC

c) Mahira S., Kommineni N., Husain G. M., Khan W., Biomed. Pharmacother. 2019, 110, 803; PubMed

d) Sun B., Ghosh S., He X., Huang W.‐C., Quinn B., Tian M., Jahagirdar D., Mabrouk M. T., Ortega J., Zhang Y., Nano Res. 2022, 15, 4302.

a) Ahmad A., Sheikh S., Paithankar M., Deshpande G., Lakshmaiah K., Maksud T. M., Khatri A., Kale P., Patel R., Barkate H., Ahmad I., J. Clin. Oncol. 2016, 34; PubMed

b) Chen W., Guo M., Wang S., Drug Dev. Ind. Pharm. 2016, 42, 1968; PubMed

c) Ren T., Wang Q., Xu Y., Cong L., Gou J., Tao X., Zhang Y., He H., Yin T., Zhang H., Zhang Y., Tang X., J. Control Release 2018, 269, 423; PubMed

d) Kommineni N., Saka R., Bulbake U., Khan W., Chem. Phys. Lipids 2019, 224, 104707; PubMed

e) Zhao Z., Li Y., Liu H., Jain A., Patel P. V., Cheng K., Sci. Adv. 2020, 6, eabb0616. PubMed PMC

a) Zhou G., Jin X., Zhu P., Yao J. U., Zhang Y., Teng L., Lee R. J., Zhang X., Hong W., Anticancer Res. 2016, 36, 1649; PubMed

b) Qu N., Lee R. J., Sun Y., Cai G., Wang J., Wang M., Lu J., Meng Q., Teng L., Wang D., Teng L., Int. J. Nanomedicine 2016, 11, 3451; PubMed PMC

c) Sun Y., Zhao Y., Teng S., Hao F., Zhang H., Meng F., Zhao X., Zheng X., Bi Y., Yao Y., Lee R. J., Teng L., Int. J. Nanomedicine 2019, 14, 135; PubMed PMC

d) Qu N., Sun Y., Xie J., Teng L., Anticancer Agents Med. Chem. 2017, 17, 294; PubMed

e) Meng F., Sun Y., Lee R. J., Wang G., Zheng X., Zhang H., Fu Y., Yan G., Wang Y., Deng W., Parks E., Kim B. Y. S., Yang Z., Jiang W., Teng L., Cancers 2019, 11, 1571. PubMed PMC

a) Chen Y., Deng Y., Zhu C., Xiang C., Biomed. Pharmacother. 2020, 127, 110181; PubMed

b) Fusser M., Øverbye A., Pandya A. D., Mørch Ý., Borgos S. E., Kildal W., Snipstad S., Sulheim E., Fleten K. G., Askautrud H. A., Engebraaten O., Flatmark K., Iversen T. G., Sandvig K., Skotland T., Mælandsmo G. M., J. Control Release 2019, 293, 183; PubMed

c) Sulheim E., Mørch Y., Snipstad S., Borgos S. E., Miletic H., Bjerkvig R., Davies C. L., Åslund A. K. O., Nanotheranostics 2019, 3, 103. PubMed PMC

a) Xue P., Liu D., Wang J., Zhang N., Zhou J., Li L., Guo W., Sun M., Han X., Wang Y., Bioconjug. Chem. 2016, 27, 1360; PubMed

b) Bensaid F., Thillaye du Boullay O., Amgoune A., Pradel C., Harivardhan Reddy L., Didier E., Sablé S., Louit G., Bazile D., Bourissou D., Biomacromolecules 2013, 14, 1189; PubMed

c) Hoang B., Ernsting M. J., Tang W. S., Bteich J., Undzys E., Kiyota T., Li S. D., Cancer Lett. 2017, 410, 169; PubMed

d) Xie B., Wan J., Chen X., Han W., Wang H., Mol. Cancer Ther. 2020, 19, 822; PubMed

e) Wan J., Qiao Y., Chen X., Wu J., Zhou L., Zhang J., Fang S., Wang H., Adv. Funct. Mater. 2018, 28, 1804229.

Prausnitz M. R., Langer R., Nat. Biotechnol. 2008, 26, 1261. PubMed PMC

Panchagnula R., Desu H., Jain A., Khandavilli S., J. Pharm. Sci. 2004, 93, 2177. PubMed

Qiu Y., Gao Y., Hu K., Li F., J. Control Release 2008, 129, 144. PubMed

a) Alexander A., Dwivedi S., Ajazuddin, T. K. G. , Saraf S., Saraf S., Tripathi D. K., J. Control Release 2012, 164, 26; PubMed

b) Kollerup Madsen B., Hilscher M., Zetner D., Rosenberg J., F1000Res. 2018, 7, 1746. PubMed PMC

Marren K., Phys. Sportsmed. 2011, 39, 75. PubMed

Thiele J. J., Ekanayake‐Mudiyanselage S., Mol. Aspects Med. 2007, 28, 646. PubMed

Dong Y.‐H., Guo Y.‐H., Gu X.‐B., Ai Zheng 2009, 28, 1114. PubMed

Prasad K. N., Edwards‐Prasad J., Cancer Res. 1982, 42, 550. PubMed

Bonferoni M. C., Riva F., Invernizzi A., Dellera E., Sandri G., Rossi S., Marrubini G., Bruni G., Vigani B., Caramella C., Ferrari F., Eur. J. Pharm. Biopharm. 2018, 123, 31. PubMed

Vrignaud P., Semiond D., Benning V., Beys E., Bouchard H., Gupta S., Drug Des. Devel Ther. 2014, 8, 1851. PubMed PMC

Abraham M. J., Murtola T., Schulz R., Páll S., Smith J. C., Hess B., Lindahl E., SoftwareX 2015, 1–2, 19.

Shirts M. R., Pitera J. W., Swope W. C., Pande V. S., J. Chem. Phys. 2003, 119, 5740.

Lu T., Molclus program, Version 1.9.9.9, http://www.keinsci.com/research/molclus.html (accessed: March 2022).

Frisch G. W. T. M. J., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Petersson G. A., Nakatsuji H., Li X., Caricato M., Marenich A., Bloino J., Janesko B. G., Gomperts R., Mennucci B., Hratchian H. P., Ortiz J. V., Izmaylov A. F., Sonnenberg J. L., Williams‐Young D., Ding F., Lipparini F., Egidi F., Goings J., Peng B., Petrone A., Henderson T., Ranasinghe D., Zakrzewski V. G., et al., Wallingford CT 2016.

Lu T., Chen Q., J. Comput. Chem. 2022, 43, 539. PubMed

Lu T., Chen F., J. Comput. Chem. 2012, 33, 580. PubMed

a) Kilfoyle B. E., Sheihet L., Zhang Z., Laohoo M., Kohn J., Michniak‐Kohn B. B., J. Control Release 2012, 163, 18; PubMed PMC

b) Tosta F. V., Andrade L. M., Mendes L. P., Anjos J. L. V., Alonso A., Marreto R. N., Lima E. M., Taveira S. F., J. Nanopart. Res 2014, 16, 2782;

c) Pepe D., Carvalho V. F., McCall M., de Lemos D. P., Lopes L. B., Int. J. Nanomedicine 2016, 11, 2009. PubMed PMC

Haq M. I., Smith E., John D. N., Kalavala M., Edwards C., Anstey A., Morrissey A., Birchall J. C., Biomed. Microdevices 2009, 11, 35. PubMed

Hu Q., Shang L., Wang M., Tu K., Hu M., Yu Y., Xu M., Kong L., Guo Y., Zhang Z., Adv. Healthcare Mater. 2020, 9, 1901858. PubMed

Lindorff‐Larsen K., Piana S., Palmo K., Maragakis P., Klepeis J. L., Dror R. O., Shaw D. E., Proteins: Struct., Funct., Bioinf. 2010, 78, 1950. PubMed PMC

Martínez L., Andrade R., Birgin E. G., Martínez J. M., J. Comput. Chem. 2009, 30, 2157. PubMed

a) Wang J., Wang W., Kollman P. A., Case D. A., J Mol Graph Model 2006, 25, 247; PubMed

b) Wang J., Wolf R. M., Caldwell J. W., Kollman P. A., Case D. A., J. Comput. Chem. 2004, 25, 1157; PubMed

c) Sousa da Silva A. W., Vranken W. F., BMC Res. Notes 2012, 5, 367. PubMed PMC

Stephens P. J., Devlin F. J., Chabalowski C. F., Frisch M. J., J. Phys. Chem. 1994, 98, 11623.

a) Ditchfield R., Hehre W. J., Pople J. A., J. Chem. Phys. 1971, 54, 724;

b) Hariharan P. C., Pople J. A., Theor. Chim. Acta 1973, 28, 213;

c) Hehre W. J., Ditchfield R., Pople J. A., J. Chem. Phys. 1972, 56, 2257.

Krishnan R., Binkley J. S., Seeger R., Pople J. A., J. Chem. Phys. 1980, 72, 650.

Grimme S., Antony J., Ehrlich S., Krieg H., J. Chem. Phys. 2010, 132. PubMed

Humphrey W., Dalke A., Schulten K., J. Mol. Graph. 1996, 14, 33. PubMed

Korth M., J. Chem. Theory Comput. 2010, 6, 3808.

MOPAC2016, J. J. P. Stewart , Stewart Computational Chemistry, Colorado Springs, CO, USA.

Bannwarth C., Ehlert S., Grimme S., J. Chem. Theory Comput. 2019, 15, 1652. PubMed

Semiempirical Extended Tight‐Binding Program Package Xtb. https://github.com/grimme‐lab/xtb/releases (accessed: August 2022).

Lu T., Liu Z., Chen Q., Mater. Sci. Eng., B 2021, 273, 115425.