Antiproliferative Activity and VEGF Expression Reduction in MCF7 and PC-3 Cancer Cells by Paclitaxel and Imatinib Co-encapsulation in Folate-Targeted Liposomes
- 436 Downloads
Co-encapsulation of anticancer drugs paclitaxel and imatinib in nanocarriers is a promising strategy to optimize cancer treatment. Aiming to combine the cytotoxic and antiangiogenic properties of the drugs, a liposome formulation targeted to folate receptor co-encapsulating paclitaxel and imatinib was designed in this work. An efficient method was optimized for the synthesis of the lipid anchor DSPE-PEG(2000)-folic acid (FA). The structure of the obtained product was confirmed by RMN, FT-IR, and ESI-MS techniques. A new analytical method was developed and validated for simultaneous quantification of the drugs by liquid chromatography. Liposomes, composed of phosphatidylcholine, cholesterol, and DSPE-mPEG(2000), were prepared by extrusion. Their surface was modified by post-insertion of DSPE-PEG(2000)-FA. Reaction yield for DSPE-PEG(2000)-FA synthesis was 87%. Liposomes had a mean diameter of 122.85 ± 1.48 nm and polydispersity index of 0.19 ± 0.01. Lyophilized formulations remained stable for 60 days in terms of size and drug loading. FA-targeted liposomes had a higher effect on MCF7 cell viability reduction (p < 0.05) when compared with non-targeted liposomes and free paclitaxel. On PC-3 cells, viability reduction was greater (p < 0.01) when cells were exposed to targeted vesicles co-encapsulating both drugs, compared with the non-targeted formulation. VEGF gene expression was reduced in MCF7 and PC-3 cells (p < 0.0001), with targeted vesicles exhibiting better performance than non-targeted liposomes. Our results demonstrate that multifunctional liposomes associating molecular targeting and multidrug co-encapsulation are an interesting strategy to achieve enhanced internalization and accumulation of drugs in targeted cells, combining multiple antitumor strategies.
KEY WORDSliposomes co-encapsulation folate receptor tumor targeting VEGF
This work was financially supported by the following Brazilian research funding agencies: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Pesquisas (FINEP), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundação de Apoio à Pesquisa da Universidade Federal de Goiás (FUNAPE), and Fundação de Apoio à Pesquisa do Estado de Goiás (FAPEG). The authors would like to thank Prof. Dr. Cecília Maria Alves de Oliveira and Dr. Monique Ferreira Marques from the Chemistry Institute/Federal University of Goias, for the assistance with synthesis and chemical characterization of the phospholipid anchor.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 4.Touchefeu Y, Montassier E, Nieman K, Gastinne T, Potel G, des Bruley Varannes S, et al. Systematic review: the role of the gut microbiota in chemotherapy- or radiation-induced gastrointestinal mucositis—current evidence and potential clinical applications. Aliment Pharmacol Ther. 2014;40:409–21. doi: 10.1111/apt.12878.PubMedGoogle Scholar
- 13.Tardi PG, Gallagher RC, Johnstone S, Harasym N, Webb M, Bally MB, et al. Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo. Biochim Biophys Acta. 2007;1768:678–87. doi: 10.1016/j.bbamem.2006.11.014.CrossRefPubMedGoogle Scholar
- 16.Mundhenke C, Weigel MT, Sturner KH, Roesel F, Meinhold-Heerlein I, Bauerschlag DO, et al. Novel treatment of ovarian cancer cell lines with Imatinib mesylate combined with paclitaxel and carboplatin leads to receptor-mediated antiproliferative effects. J Cancer Res Clin Oncol. 2008;134:1397–405. doi: 10.1007/s00432-008-0408-0.CrossRefPubMedGoogle Scholar
- 23.Guideline IHT. Validation of analytical procedures: text and methodology Q2(R1). 2005; Available from: https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q2_R1/Step4/Q2_R1__Guideline.pdf. Accessed 05 May 2017
- 30.Kang MJ, Park SH, Kang MH, Park MJ, Choi YW. Folic acid-tethered pep-1 peptide-conjugated liposomal nanocarrier for enhanced intracellular drug delivery to cancer cells: conformational characterization and in vitro cellular uptake evaluation. Int J Nanomedicine. 2013;8:1155–65. doi: 10.2147/IJN.S39491.CrossRefPubMedPubMedCentralGoogle Scholar
- 52.Schultz JD, Rotunno S, Riedel F, Anders C, Erben P, Hofheinz RD, et al. Synergistic effects of imatinib and carboplatin on VEGF, PDGF and PDGF-Ralpha/ss expression in squamous cell carcinoma of the head and neck in vitro. Int J Oncol. 2011;38:1001–12. doi: 10.3892/ijo.2011.912.CrossRefPubMedGoogle Scholar