We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine
Research Articlecc iconby icon

Efficacy of DOPE/DC-cholesterol liposomes and GCPQ micelles as AZD6244 nanocarriers in a 3D colorectal cancer in vitro model

    Víctor López-Dávila

    Cancer Nanotechnology Group, University College London, Division of Surgery & Interventional Science, Royal Free Campus, London, NW3 2PF, UK

    ,
    Tarig Magdeldin

    Cancer Nanotechnology Group, University College London, Division of Surgery & Interventional Science, Royal Free Campus, London, NW3 2PF, UK

    Institute of Orthopaedics & Musculoskeletal Sciences, University College London, Division of Surgery & Interventional Science, Stanmore Campus, HA7 4LP, UK

    ,
    Hazel Welch

    Cancer Nanotechnology Group, University College London, Division of Surgery & Interventional Science, Royal Free Campus, London, NW3 2PF, UK

    ,
    Miriam Victoria Dwek

    Department of Biomedical Sciences, Faculty of Science & Technology, University of Westminster, 115 New Cavendish Street, London, W1W 6UW, UK

    ,
    Ijeoma Uchegbu

    School of Pharmacy, University College London, 29–39 Brunswick Square, London, WC1N 1AX, UK

    &
    Marilena Loizidou

    *Author for correspondence:

    E-mail Address: m.loizidou@ucl.ac.uk

    Cancer Nanotechnology Group, University College London, Division of Surgery & Interventional Science, Royal Free Campus, London, NW3 2PF, UK

    Published Online:https://doi.org/10.2217/nnm.15.206

    Aim: In this work, we use cationic organic nanocarriers as chemotherapy delivery platforms and test them in a colorectal cancer 3D in vitro model. Materials & methods: We used 3beta-(N-[N′,N′-dimethylaminoethane]carbamoyl])cholesterol (DC-chol) and dioleoylphosphatidylethanolamine (DOPE) liposomes and N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ) micelles, to deliver AZD6244, a MEK inhibitor, to HCT116 cells cultured as monolayers and in 3D in vitro cancer models (tumoroids). Results: Nanoparticle-mediated drug delivery was superior to the free drug in monolayer experiments and despite their therapeutic effect being hindered by poor diffusion through the cancer mass, GCPQ micelles were also superior in tumoroids. Conclusion: These results support the role of nanoparticles in improving drug delivery and highlight the need to include 3D cancer models in early phases of drug development.

    References

    • 1 Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J. Clin. 61(2), 69–90 (2011).
    • 2 Ostman A, Augsten M. Cancer-associated fibroblasts and tumor growth–bystanders turning into key players. Curr. Opin. Genet. Dev. 19(1), 67–73 (2009).
    • 3 Yamada KM, Cukierman E. Modeling tissue morphogenesis and cancer in 3D. Cell 130(4), 601–610 (2007).
    • 4 Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature 432(7015), 332–337 (2004).
    • 5 Rhee S, Grinnell F. Fibroblast mechanics in 3D collagen matrices. Adv. Drug Deliv. Rev. 59(13), 1299–1305 (2007).
    • 6 Halliwell B. Oxidative stress in cell culture: an under-appreciated problem? FEBS Lett. 540(1–3), 3–6 (2003).
    • 7 Voskoglou-Nomikos T, Pater JL, Seymour L. Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. Clin. Cancer Res. 9(11), 4227–4239 (2003).
    • 8 Sharpless NE, Depinho RA. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug Discov. 5(9), 741–754 (2006).
    • 9 Magdeldin T, Lopez-Davila V, Villemant C et al. The efficacy of cetuximab in a tissue-engineered three-dimensional in vitro model of colorectal cancer. J. Tissue Eng. 5, 2041731414544183 (2014).
    • 10 Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J. Natl Cancer Inst. 99(19), 1441–1454 (2007).
    • 11 Mikhail AS, Eetezadi S, Allen C. Multicellular tumor spheroids for evaluation of cytotoxicity and tumor growth inhibitory effects of nanomedicines in vitro: a comparison of docetaxel-loaded block copolymer micelles and Taxotere(R). PLoS ONE 8(4), e62630 (2013).
    • 12 Hickman JA, Graeser R, De Hoogt R et al. Three-dimensional models of cancer for pharmacology and cancer cell biology: capturing tumor complexity in vitro/ex vivo. Biotechnol. J. 9(9), 1115–1128 (2014).
    • 13 Huang K, Ma H, Liu J et al. Size-dependent localization and penetration of ultrasmall gold nanoparticles in cancer cells, multicellular spheroids, and tumors in vivo. ACS Nano 6(5), 4483–4493 (2012).
    • 14 Kunz-Schughart LA, Kreutz M, Knuechel R. Multicellular spheroids: a three-dimensional in vitro culture system to study tumour biology. Int. J. Exp. Pathol. 79(1), 1–23 (1998).
    • 15 Holliday DL, Brouilette KT, Markert A, Gordon LA, Jones JL. Novel multicellular organotypic models of normal and malignant breast: tools for dissecting the role of the microenvironment in breast cancer progression. Breast Cancer Res. 11(1), R3 (2009).
    • 16 Suri S, Schmidt CE. Cell-laden hydrogel constructs of hyaluronic acid, collagen, and laminin for neural tissue engineering. Tissue Eng. A 16(5), 1703–1716 (2010).
    • 17 Gurski LA, Jha AK, Zhang C, Jia X, Farach-Carson MC. Hyaluronic acid-based hydrogels as 3D matrices for in vitro evaluation of chemotherapeutic drugs using poorly adherent prostate cancer cells. Biomaterials 30(30), 6076–6085 (2009).
    • 18 Christopher S, Szot CFB, Paul Gatenholm, Marissa Nichole Rylander, Freeman Joseph W. Investigation of cancer cell behavior on nanofibrous scaffolds. Mater. Sci. Eng. C 31(1), 37–42 (2011).
    • 19 Ricketts Kate PM, Umber Cheema, Agata Nyga et al. A 3D In vitro cancer model as a platform for nanoparticle uptake and imaging investigations. Small 10(19), 3954–3961 (2014).
    • 20 Nyga A, Loizidou M, Emberton M, Cheema U. A novel tissue engineered three-dimensional in vitro colorectal cancer model. Acta Biomater. 9(8), 7917–7926 (2013).
    • 21 Lopez-Davila V, Seifalian AM, Loizidou M. Organic nanocarriers for cancer drug delivery. Curr. Opin. Pharmacol. 12(4), 414–419 (2012).
    • 22 Hino M, Ichihara H, Matsumoto Y, Ueoka R. Anti-tumor effects of cationic hybrid liposomes against colon carcinoma along with apoptosis in vitro. Biol. Pharm. Bull. 35(11), 2097–2101 (2012).
    • 23 Erdog A, Putra Limasale YD, Keskin D, Tezcaner A, Banerjee S. In vitro characterization of a liposomal formulation of celecoxib containing 1,2-distearoyl-sn-glycero-3-phosphocholine, cholesterol, and polyethylene glycol and its functional effects against colorectal cancer cell lines. J. Pharm. Sci. 102(10), 3666–3677 (2013).
    • 24 Casado A, Sagrista ML, Mora M. Formulation and in vitro characterization of thermosensitive liposomes for the delivery of irinotecan. J. Pharm. Sci. 103(10), 3127–3138 (2014).
    • 25 Guo S, Huang L. Nanoparticles containing insoluble drug for cancer therapy. Biotechnol. Adv. 32(4), 778–788 (2014).
    • 26 Zhang Y, Li H, Sun J et al. DC-Chol/DOPE cationic liposomes: a comparative study of the influence factors on plasmid pDNA and siRNA gene delivery. Int. J. Pharm. 390(2), 198–207 (2010).
    • 27 Yang S, Chen J, Zhao D, Han D, Chen X. Comparative study on preparative methods of DC-Chol/DOPE liposomes and formulation optimization by determining encapsulation efficiency. Int. J. Pharm. 434(1–2), 155–160 (2012).
    • 28 Ciani L, Ristori S, Salvati A, Calamai L, Martini G. DOTAP/DOPE and DC-Chol/DOPE lipoplexes for gene delivery: zeta potential measurements and electron spin resonance spectra. Biochim. Biophys. Acta 1664(1), 70–79 (2004).
    • 29 Qu X, Khutoryanskiy VV, Stewart A et al. Carbohydrate-based micelle clusters which enhance hydrophobic drug bioavailability by up to 1 order of magnitude. Biomacromolecules 7(12), 3452–3459 (2006).
    • 30 Siew A, Le H, Thiovolet M, Gellert P, Schatzlein A, Uchegbu I. Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol. Pharm. 9(1), 14–28 (2012).
    • 31 Lalatsa A, Garrett NL, Ferrarelli T, Moger J, Schatzlein AG, Uchegbu IF. Delivery of peptides to the blood and brain after oral uptake of quaternary ammonium palmitoyl glycol chitosan nanoparticles. Mol. Pharm. 9(6), 1764–1774 (2012).
    • 32 Pelaz B, Charron G, Pfeiffer C et al. Interfacing engineered nanoparticles with biological systems: anticipating adverse nano-bio interactions. Small 9(9–10), 1573–1584 (2013).
    • 33 Dokka S, Toledo D, Shi X, Castranova V, Rojanasakul Y. Oxygen radical-mediated pulmonary toxicity induced by some cationic liposomes. Pharm. Res. 17(5), 521–525 (2000).
    • 34 Lee WL, Guo WM, Ho VH et al. Inhibition of 3-D tumor spheroids by timed-released hydrophilic and hydrophobic drugs from multilayered polymeric microparticles. Small 10(19), 3986–3996 (2014).
    • 35 Oishi M, Nagasaki Y, Nishiyama N et al. Enhanced growth inhibition of hepatic multicellular tumor spheroids by lactosylated poly(ethylene glycol)-siRNA conjugate formulated in PEGylated polyplexes. ChemMedChem 2(9), 1290–1297 (2007).
    • 36 Perche F, Patel NR, Torchilin VP. Accumulation and toxicity of antibody-targeted doxorubicin-loaded PEG-PE micelles in ovarian cancer cell spheroid model. J. Control. Release 164(1), 95–102 (2012).
    • 37 Mozafari MR. Nanoliposomes: preparation and analysis. Methods Mol. Biol. 605, 29–50 (2010).
    • 38 RA Brown MW, Chuo CB, Cheema U, Nazhat SN. Ultrarapid engineering of biomimetic materials and tissues: fneabrication of nano- and microstructures by plastic compression. Adv. Funct. Mater. 15(11), 1762–1770 (2005).
    • 39 Ciombor KK, Bekaii-Saab T. Selumetinib for the treatment of cancer. Expert Opin. Invest. Drugs 24(1), 111–123 (2015).
    • 40 Basu S, Harfouche R, Soni S, Chimote G, Mashelkar RA, Sengupta S. Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy. Proc. Natl Acad. Sci. USA 106(19), 7957–7961 (2009).
    • 41 Kang SH, Cho HJ, Shim G et al. Cationic liposomal co-delivery of small interfering RNA and a MEK inhibitor for enhanced anticancer efficacy. Pharm. Res. 28(12), 3069–3078 (2011).
    • 42 Lin J, Zhang H, Chen Z, Zheng Y. Penetration of lipid membranes by gold nanoparticles: insights into cellular uptake, cytotoxicity, and their relationship. ACS Nano 4(9), 5421–5429 (2010).
    • 43 Pisani M, Mobbili G, Paolo Bruni. Neutral Liposomes and DNA transfection. In: Non-Viral Gene Therapy. Yuan X-B (Ed.). Intech, Rijeka, Croatia (2011).
    • 44 Ichihara H, Hino M, Umebayashi M, Matsumoto Y, Ueoka R. Intravenous injection of hybrid liposomes suppresses the liver metastases in xenograft mouse models of colorectal cancer in vivo. Eur. J. Med. Chem. 57, 143–148 (2012).
    • 45 Murrell MP, Voituriez R, Joanny JF, Nassoy P, Sykes C, Gardel ML. Liposome adhesion generates traction stress. Nat. Phys. 10(2), 163–169 (2014).
    • 46 Shah V, Taratula O, Garbuzenko OB et al. Genotoxicity of different nanocarriers: possible modifications for the delivery of nucleic acids. Curr. Drug Discov. Technol. 10(1), 8–15 (2013).
    • 47 Andar AU, Hood RR, Vreeland WN, Devoe DL, Swaan PW. Microfluidic preparation of liposomes to determine particle size influence on cellular uptake mechanisms. Pharm. Res. 31(2), 401–413 (2014).
    • 48 Polo ML, Arnoni MV, Riggio M, Wargon V, Lanari C, Novaro V. Responsiveness to PI3K and MEK inhibitors in breast cancer. Use of a 3D culture system to study pathways related to hormone independence in mice. PLoS ONE 5(5), e10786 (2010).
    • 49 Caputo E, Miceli R, Motti ML et al. AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment. J. Transl. Med. 12, 216 (2014).
    • 50 Ferguson J, Arozarena I, Ehrhardt M, Wellbrock C. Combination of MEK and SRC inhibition suppresses melanoma cell growth and invasion. Oncogene 32(1), 86–96 (2013).
    • 51 Chambers KF, Mosaad EM, Russell PJ, Clements JA, Doran MR. 3D Cultures of prostate cancer cells cultured in a novel high-throughput culture platform are more resistant to chemotherapeutics compared with cells cultured in monolayer. PLoS ONE 9(11), e111029 (2014).
    • 52 Minchinton AI, Tannock IF. Drug penetration in solid tumours. Nat. Rev. Cancer 6(8), 583–592 (2006).
    • 53 Xiang X, Phung Y, Feng M et al. The development and characterization of a human mesothelioma in vitro 3D model to investigate immunotoxin therapy. PLoS ONE 6(1), e14640 (2011).