Development of podophyllotoxin‑loaded nanostructured lipid carriers for the treatment of condyloma acuminatum

Gao,Yan; Han,Kai; Wang,Qi; Hu,Zhili; Liu,Qingxiu; Liu,Lishi; Zeng,Kang

doi:10.3892/mmr.2018.8696

Development of podophyllotoxin‑loaded nanostructured lipid carriers for the treatment of condyloma acuminatum

Authors:
- Yan Gao
- Kai Han
- Qi Wang
- Zhili Hu
- Qingxiu Liu
- Lishi Liu
- Kang Zeng
View Affiliations

Affiliations: Department of Dermatology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
Published online on: March 7, 2018 https://doi.org/10.3892/mmr.2018.8696
Pages: 6506-6514
Copyright: © Gao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Condyloma acuminatum (CA) is a common sexually transmitted disease caused by human papillomavirus (HPV). Podophyllotoxin (POD), a cytotoxic compound, is able to effectively treat HPV; however, the severe irritation side effects of POD restrict its use as a treatment for CA. The aim of the present study was to construct novel POD‑loaded nanostructured nanolipid carriers (POD‑NLCs) and evaluate their physicochemical characteristics and cytotoxicity. POD‑NLCs (0.5%) were prepared using emulsion‑evaporation and low temperature‑solidification methods with optimized conditions and preparations. Subsequently, the POD‑NLCs were physicochemically characterized and their in vitro and in vivo release efficiencies and in vitro cytotoxicity were studied. The prepared POD‑NLCs had an average particle size, ζ potential, polydispersity index and encapsulation efficacy of 178.5±20 nm, ‑27±0.5 mV, 0.18±0.01 and 82.9±2%, respectively. In vitro and in vivo release studies demonstrated that POD‑NLCs are able to provide sustained drug delivery for 72 h in vitro and 10 h in the mucosa. Compared with a tincture formulation of POD (POD‑T), POD‑NLC induced less inflammatory cytokine production in the cervical mucous and led to a decreased histopathological score. In addition, a cytotoxicity assay demonstrated that inhibition of the POD‑NLCs was 98.4% at 24 h and remained >98% up to 72 h. Furthermore, more cells were arrested in the G2/M phase of the cell cycle following POD‑NLC treatment compared with the POD‑T treatment. The present study provides evidence that POD‑NLC is a promising delivery system for the treatment of CA.

View Figures

View References

1	Ball SL, Winder DM, Vaughan K, Hanna N, Levy J, Sterling JC, Stanley MA and Goon PK: Analyses of human papillomavirus genotypes and viral loads in anogenital warts. J Med Virol. 83:1345–1350. 2011. View Article : Google Scholar : PubMed/NCBI
2	Park IU, Introcaso C and Dunne EF: Human papillomavirus and genital warts: A review of the evidence for the 2015 centers for disease control and prevention sexually transmitted diseases treatment guidelines. Clin Infect Dis. 61 Suppl 8:S849–S855. 2015. View Article : Google Scholar : PubMed/NCBI
3	Lamos C, Mihaljevic C, Aulmann S, Bruckner T, Domschke C, Wallwiener M, Paringer C, Fluhr H, Schott S, Dinkic C, et al: Detection of human papillomavirus infection in patients with vaginal intraepithelial neoplasia. PLoS One. 11:e01673862016. View Article : Google Scholar : PubMed/NCBI
4	Fu Xi L, Schiffman M, Ke Y, Hughes JP, Galloway DA, He Z, Hulbert A, Winer RL, Koutsky LA and Kiviat NB: Type-dependent association between risk of cervical intraepithelial neoplasia and viral load of oncogenic human papillomavirus types other than types 16 and 18. Int J Cancer. 140:1747–1756. 2017. View Article : Google Scholar : PubMed/NCBI
5	Gordaliza M, Garcia PA, del Corral JM, Castro MA and Gómez-Zurita MA: Podophyllotoxin: Distribution, sources, applications and new cytotoxic derivatives. Toxicon. 44:441–459. 2004. View Article : Google Scholar : PubMed/NCBI
6	Lacey CJ, Woodhall SC, Wikstrom A and Ross J: 2012 European guideline for the management of anogenital warts. J Eur Acad Dermatol Venereol. 27:e263–e270. 2013. View Article : Google Scholar : PubMed/NCBI
7	Karuppaiya P and Tsay HS: Therapeutic values, chemical constituents and toxicity of Taiwanese Dysosma pleiantha-a review. Toxicol Lett. 236:90–97. 2015. View Article : Google Scholar : PubMed/NCBI
8	Deng JF, Huang CC and Lee YJ: Toxicokinetic parameters in the management of poisoning: An example of podophyllotoxin intoxication. J Toxicol Sci. 23 Suppl 2:S205–S208. 1998. View Article : Google Scholar
9	Karimunnisa S and Atmaram P: Mucoadhesive nanoliposomal formulation for vaginal delivery of an antifungal. Drug Dev Ind Pharm. 39:1328–1337. 2013. View Article : Google Scholar : PubMed/NCBI
10	Puglia C, Blasi P, Rizza L, Schoubben A, Bonina F, Rossi C and Ricci M: Lipid nanoparticles for prolonged topical delivery: An in vitro and in vivo investigation. Int J Pharm. 357:295–304. 2008. View Article : Google Scholar : PubMed/NCBI
11	Liu D, Liu Z, Wang L, Zhang C and Zhang N: Nanostructured lipid carriers as novel carrier for parenteral delivery of docetaxel. Colloids Surf B Biointerfaces. 85:262–269. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhao J, Piao X, Shi X, Si A, Zhang Y and Feng N: Podophyllotoxin-loaded nanostructured lipid carriers for skin targeting: In vitro and in vivo studies. Molecules. 21:pii: E1549. 2016. View Article : Google Scholar
13	Rajinikanth PS and Chellian J: Development and evaluation of nanostructured lipid carrier-based hydrogel for topical delivery of 5-fluorouracil. Int J Nanomedicine. 11:5067–5077. 2016. View Article : Google Scholar : PubMed/NCBI
14	Zhang S, Wang J and Pan J: Baicalin-loaded PEGylated lipid nanoparticles: Characterization, pharmacokinetics, and protective effects on acute myocardial ischemia in rats. Drug Deliv. 23:3696–3703. 2016. View Article : Google Scholar : PubMed/NCBI
15	Wang Y, Zhao B, Wang S, Liang Q, Cai Y, Yang F and Li G: Formulation and evaluation of novel glycyrrhizic acid micelles for transdermal delivery of podophyllotoxin. Drug Deliv. 23:1623–1635. 2016. View Article : Google Scholar : PubMed/NCBI
16	Owen DH and Katz DF: A vaginal fluid simulant. Contraception. 59:91–95. 1999. View Article : Google Scholar : PubMed/NCBI
17	Holt JD, Cameron D, Dias N, Holding J, Muntendam A, Oostebring F, Dreier P, Rohan L and Nuttall J: The sheep as a model of preclinical safety and pharmacokinetic evaluations of candidate microbicides. Antimicrob Agents Chemother. 59:3761–3770. 2015. View Article : Google Scholar : PubMed/NCBI
18	Koshiol J, Sklavos M, Wentzensen N, Kemp T, Schiffman M, Dunn ST, Wang SS, Walker JL, Safaeian M, Zuna RE, et al: Evaluation of a multiplex panel of immune-related markers in cervical secretions: A methodologic study. Int J Cancer. 134:411–425. 2014. View Article : Google Scholar : PubMed/NCBI
19	Wang Q, Han K, Li X, Xiao Y and Zeng K: Role of endoplasmic reticulum stress pathway in podophyllotoxin nanostructured lipid carriers-induced apoptosis of VK2/E6E7 cells. Nan Fang Yi Ke Da Xue Xue Bao. 34:832–836. 2014.(In Chinese). PubMed/NCBI
20	D'Cruz OJ, Erbeck D and Uckun FM: A study of the potential of the pig as a model for the vaginal irritancy of benzalkonium chloride in comparison to the nonirritant microbicide PHI-443 and the spermicide vanadocene dithiocarbamate. Toxicol Pathol. 33:465–476. 2005. View Article : Google Scholar : PubMed/NCBI
21	Pachman DR, Barton DL, Clayton AC, McGovern RM, Jefferies JA, Novotny PJ, Sloan JA, Loprinzi CL and Gostout BS: Randomized clinical trial of imiquimod: An adjunct to treating cervical dysplasia. Am J Obstet Gynecol. 206:42.e1–7. 2012. View Article : Google Scholar
22	Fichorova RN, Mendonca K, Yamamoto HS, Murray R, Chandra N and Doncel GF: A quantitative multiplex nuclease protection assay reveals immunotoxicity gene expression profiles in the rabbit model for vaginal drug safety evaluation. Toxicol Appl Pharmacol. 285:198–206. 2015. View Article : Google Scholar : PubMed/NCBI
23	Olerile LD, Liu Y, Zhang B, Wang T, Mu S, Zhang J, Selotlegeng L and Zhang N: Near-infrared mediated quantum dots and paclitaxel co-loaded nanostructured lipid carriers for cancer theragnostic. Colloids Surf B Biointerfaces. 150:121–130. 2017. View Article : Google Scholar : PubMed/NCBI
24	Gutierrez-Xicotencatl L, Salazar-Piña DA, Pedroza-Saavedra A, Chihu-Amparan L, Rodriguez-Ocampo AN, Maldonado-Gama M and Esquivel-Guadarrama FR: Humoral immune response against human papillomavirus as source of biomarkers for the prediction and detection of cervical cancer. Viral Immunol. 29:83–94. 2016. View Article : Google Scholar : PubMed/NCBI
25	Bestehorn K, Bestehorn M and Fleck E: Influence of different approaches of aortic valve replacement on the incidence of post-operative delirium in intermediate risk patients-a matched pair analysis. Curr Med Res Opin. 31:2157–2163. 2015. View Article : Google Scholar : PubMed/NCBI
26	das Neves J, Araújo F, Andrade F, Amiji M, Bahia MF and Sarmento B: Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. Pharm Res. 31:1834–1845. 2014. View Article : Google Scholar : PubMed/NCBI
27	Lai SK, O'Hanlon DE, Harrold S, Man ST, Wang YY, Cone R and Hanes J: Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc Natl Acad Sci USA. 104:pp. 482–1487. 2007;
28	Khutoryanskiy VV: Advances in mucoadhesion and mucoadhesive polymers. Macromol Biosci. 11:748–764. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ramineni SK, Dziubla TD, Cunningham LL Jr and Puleo DA: Local delivery of imiquimod in hamsters using mucoadhesive films and their residence time in human patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 118:665–673. 2014. View Article : Google Scholar : PubMed/NCBI
30	Franasiak JM and Scott RT Jr: Reproductive tract microbiome in assisted reproductive technologies. Fertil Steril. 104:1364–1371. 2015. View Article : Google Scholar : PubMed/NCBI
31	Chen H, Chang X, Du D, Liu W, Liu J, Weng T, Yang Y, Xu H and Yang X: Podophyllotoxin-loaded solid lipid nanoparticles for epidermal targeting. J Control Release. 110:296–306. 2006. View Article : Google Scholar : PubMed/NCBI
32	Fichorova RN, Bajpai M, Chandra N, Hsiu JG, Spangler M, Ratnam V and Doncel GF: Interleukin (IL)-1, IL-6, and IL-8 predict mucosal toxicity of vaginal microbicidal contraceptives. Biol Reprod. 71:761–769. 2004. View Article : Google Scholar : PubMed/NCBI
33	Iwata T, Fujii T, Morii K, Saito M, Sugiyama J, Nishio H, Morisada T, Tanaka K, Yaguchi T, Kawakami Y and Aoki D: Cytokine profile in cervical mucosa of Japanese patients with cervical intraepithelial neoplasia. Int J Clin Oncol. 20:126–133. 2015. View Article : Google Scholar : PubMed/NCBI
34	Passmore JA, Jaspan HB and Masson L: Genital inflammation, immune activation and risk of sexual HIV acquisition. Curr Opin HIV AIDS. 11:156–162. 2016. View Article : Google Scholar : PubMed/NCBI
35	Ghate VM, Lewis SA, Prabhu P, Dubey A and Patel N: Nanostructured lipid carriers for the topical delivery of tretinoin. Eur J Pharm Biopharm. 108:253–261. 2016. View Article : Google Scholar : PubMed/NCBI
36	von Krogh G: Podophyllotoxin in serum: Absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. Sex Transm Dis. 9:26–33. 1982. View Article : Google Scholar : PubMed/NCBI
37	Peuster M, Fink C, Reckers J, Beerbaum P and von Schnakenburg C: Assessment of subacute inflammatory and proliferative response to coronary stenting in a porcine model by local gene expression studies and histomorphometry. Biomaterials. 25:957–963. 2004. View Article : Google Scholar : PubMed/NCBI
38	Sakurai H, Miki T, Imakura Y, Shibuya M and Lee KH: Metal- and photo-induced cleavage of DNA by podophyllotoxin, etoposide, and their related compounds. Mol Pharmacol. 40:965–973. 1991.PubMed/NCBI