brought to you byLaboratorio Nacional de Engenharia Civil – LNEC
Skip main navigation
Research Article

Functionalized diterpene parvifloron D-loaded hybrid nanoparticles for targeted delivery in melanoma therapy

    Catarina Oliveira Silva

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcalá, Spain

    Search for more papers by this author

    ,
    Jesús Molpeceres

    Department of Biomedical Sciences, Faculty of Pharmacy, University of Alcalá, Spain

    Search for more papers by this author

    ,
    Belén Batanero

    Department of Organic & Inorganic Chemistry, Faculty of Pharmacy, University of Alcalá, Spain

    Search for more papers by this author

    ,
    Ana Sofia Fernandes

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal

    Search for more papers by this author

    ,
    Nuno Saraiva

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    Search for more papers by this author

    ,
    João Guilherme Costa

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal

    Search for more papers by this author

    ,
    Patrícia Rijo

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal

    Search for more papers by this author

    ,
    Isabel Vitória Figueiredo

    Pharmacology & Pharmaceutical Care, Faculty of Pharmacy, Universidade de Coimbra, Portugal

    IBILI, Institute for Biomedical Imaging & Life Sciences, Universidade de Coimbra, Portugal

    Search for more papers by this author

    ,
    Pedro Faísca

    Faculty of Veterinary Medicine – Universidade Lusófona, Lisboa, Portugal

    Search for more papers by this author

    &
    Catarina Pinto Reis

    *Author for correspondence:

    E-mail Address: catarinapintoreis@ulusofona.pt

    CBiOS, Research Center for Biosciences & Health Technologies, Universidade Lusófona, Campo Grande 376, 1749–024 Lisboa, Portugal

    IBEB, Biophysics & Biomedical Engineering, Faculty of Sciences, Universidade de Lisboa, Portugal

    Search for more papers by this author

    Published Online:22 Jul 2016https://doi.org/10.4155/tde-2016-0027

    Abstract

    Aim: Parvifloron D is a natural diterpene with a broad and not selective cytotoxicity toward human tumor cells. In order to develop a targeted antimelanoma drug delivery platform for Parvifloron D, hybrid nanoparticles were prepared with biopolymers and functionalized with α-melanocyte stimulating hormone. Results/methodology: Nanoparticles were produced according to a solvent displacement method and the physicochemical properties were assessed. It was shown that Parvifloron D is cytotoxic and can induce, both as free and as encapsulated drug, cell death in melanoma cells (human A375 and mouse B16V5). Parvifloron D-loaded nanoparticles showed a high encapsulation efficiency (87%) and a sustained release profile. In vitro experiments showed the nanoparticles’ uptake and cell internalization. Conclusion: Hybrid nanoparticles appear to be a promising platform for long-term drug release, presenting the desired structure and a robust performance for targeted anticancer therapy.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Garbe C, Peris K, Hauschild A et al. Diagnosis and treatment of melanoma. European consensus-based interdisciplinary guideline – Update 2012. Eur. J. Cancer. 48(15), 2375–2390 (2012).Crossref, Medline, Google Scholar
    • 2 Eggermont AMM, Spatz A, Robert C. Cutaneous melanoma. Lancet 383(9919), 816–827. •• Describes the major advances in diagnosis and treatment of cutaneous melanoma.Crossref, Medline, Google Scholar
    • 3 Wolinsky JB, Colson YL, Grinstaff MW. Local drug delivery strategies for cancer treatment: gels, nanoparticles, polymeric films, rods, and wafers. J. Control. Rel. 159(1), 14–26 (2012). •• Reviews the applications of polymer-based drug delivery nanosystems in cancer therapy.Crossref, Medline, CAS, Google Scholar
    • 4 d'Angelo I, Conte C, Miro A, Quaglia F, Ungaro F. Core–shell nanocarriers for cancer therapy. Part I: biologically oriented design rules. Expert Opin. Drug Deliv. 11(2), 283–297 (2014).Crossref, Medline, Google Scholar
    • 5 Dianzani C, Zara GP, Maina G et al. Drug delivery nanoparticles in skin cancers. Biomed. Res. Int. 2014, Article ID 895986 (2014).Crossref, Medline, Google Scholar
    • 6 Simões MCF, Sousa JJS, Pais A. Skin cancer and new treatment perspectives: a review. Cancer Lett. 357(1), 8–42 (2015).Crossref, Medline, CAS, Google Scholar
    • 7 Zhao Q-H, Zhang Y, Liu Y et al. Anticancer effect of realgar nanoparticles on mouse melanoma skin cancer in vivo via transdermal drug delivery. Med. Oncol. 27(2), 203–212 (2010).Crossref, Medline, CAS, Google Scholar
    • 8 Weinberg BD, Blanco E, Gao J. Polymer implants for intratumoral drug delivery and cancer therapy. J. Pharm. Sci. 97(5), 1681–1702 (2008).Crossref, Medline, CAS, Google Scholar
    • 9 Liu R, Wolinsky J, Walpole J et al. Prevention of local tumor recurrence following surgery using low-dose chemotherapeutic polymer films. Ann. Surg. Oncol. 17(4), 1203–1213 (2010).Crossref, Medline, Google Scholar
    • 10 Micali G, Lacarrubba F, Nasca MR, Ferraro S, Schwartz RA. Topical pharmacotherapy for skin cancer: part II. Clinical applications. J. Am. Acad. Dermatol. 70(6), 979.e1–979.e12 (2014).Crossref, Medline, CAS, Google Scholar
    • 11 Ma M, Hao Y, Liu N et al. A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution. Int. J. Nanomedicine 7, 3389–3398 (2012).Crossref, Medline, CAS, Google Scholar
    • 12 Mangalathillam S, Rejinold NS, Nair A, Lakshmanan V-K, Nair SV, Jayakumar R. Curcumin loaded chitin nanogels for skin cancer treatment via the transdermal route. Nanoscale 4(1), 239–250 (2012).Crossref, Medline, CAS, Google Scholar
    • 13 Zhang L, He R, Gu H-C. Oleic acid coating on the monodisperse magnetite nanoparticles. Appl. Surf. Sci. 253(5), 2611–2617 (2006).Crossref, CAS, Google Scholar
    • 14 Silva CO, Rijo P, Molpeceres J et al. Polymeric nanoparticles modified with fatty acids encapsulating betamethasone for anti-inflammatory treatment. Int. J. Pharm. 493(1–2), 271–284 (2015).Crossref, Medline, CAS, Google Scholar
    • 15 Park J-H, Cho H-J, Yoon HY et al. Hyaluronic acid derivative-coated nanohybrid liposomes for cancer imaging and drug delivery. J. Control. Rel. 174(0), 98–108 (2014).Crossref, Medline, CAS, Google Scholar
    • 16 Ahrens T, Assmann V, Fieber C et al. CD44 is the principal mediator of hyaluronic-acid-induced melanoma cell proliferation. J. Invest. Dermatol. 116(1), 93–101 (2001).Crossref, Medline, CAS, Google Scholar
    • 17 Kong M, Chen XG, Kweon DK, Park HJ. Investigations on skin permeation of hyaluronic acid based nanoemulsion as transdermal carrier. Carbohydr. Polym. 86(2), 837–843 (2011).Crossref, CAS, Google Scholar
    • 18 Yang J-A, Kim E-S, Kwon JH et al. Transdermal delivery of hyaluronic acid – human growth hormone conjugate. Biomaterials 33(25), 5947–5954 (2012).Crossref, Medline, CAS, Google Scholar
    • 19 Carlson JA, Linette GP, Aplin A, Ng B, Slominski A. Melanocyte receptors: clinical implications and therapeutic relevance. Dermatol. Clin. 25(4), 541–557 (2007).Crossref, Medline, CAS, Google Scholar
    • 20 Abdel-Mottaleb MMA, Neumann D, Lamprecht A. Lipid nanocapsules for dermal application: a comparative study of lipid-based versus polymer-based nanocarriers. Eur. J. Pharm. Biopharm. 79(1), 36–42 (2010).Crossref, Google Scholar
    • 21 Bombelli FB, Webster CA, Moncrieff M, Sherwood V. The scope of nanoparticle therapies for future metastatic melanoma treatment. Lancet Oncol. 15(1), e22–e32 (2014).Crossref, Medline, CAS, Google Scholar
    • 22 Gonçalves AS, Macedo AS, Souto EB. Therapeutic nanosystems for oncology nanomedicine. Clin. Transl. Oncol. 14(12), 883–890 (2012).Crossref, Medline, CAS, Google Scholar
    • 23 Madhunapantula SV, Robertson GP. Chapter twelve – chemoprevention of melanoma. In: Advances in Pharmacology. Keiran SMS (Ed.). Academic Press, Cambridge, USA, 361–398 (2012).Google Scholar
    • 24 Simões MF, Rijo P, Duarte A, Matias D, Rodríguez B. An easy and stereoselective rearrangement of an abietane diterpenoid into a bioactive microstegiol derivative. Phytochem. Lett. 3(4), 234–237 (2010).Crossref, CAS, Google Scholar
    • 25 Burmistrova O, Simões MF, Rijo P, Quintana J, Bermejo J, Estévez F. Antiproliferative activity of abietane diterpenoids against human tumor cells. J. Nat. Prod. 76(8), 1413–1423 (2013).Crossref, Medline, CAS, Google Scholar
    • 26 Burmistrova O, Perdomo J, Simões MF, Rijo P, Quintana J, Estévez F. The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells. Phytomedicine 22(11), 1009–16 (2015). • Reports the cytotoxicity character of the natural compund parvifloron D on several cancer cell lines.Crossref, Medline, CAS, Google Scholar
    • 27 Scodeller P, Catalano PN, Salguero N, Duran H, Wolosiuk A, Soler-Illia GJAA. Hyaluronan degrading silica nanoparticles for skin cancer therapy. Nanoscale. 5(20), 9690–9698 (2013).Crossref, Medline, CAS, Google Scholar
    • 28 Chung H, Lee J, Jeong D, Han I-O, Oh E-S. Melanocortin 1 receptor regulates melanoma cell migration by controlling syndecan-2 expression. J. Biol. Chem. 287(23), 19326–19335 (2012).Crossref, Medline, CAS, Google Scholar
    • 29 Dou J, Pan M, Wen P et al. Isolation and identification of cancer stem-like cells from murine melanoma cell lines. Cell. Mol. Immunol. 4(6), 467–472 (2007).Medline, Google Scholar
    • 30 Nicoletti I, Migliorati G, Pagliacci MC, Grignani F, Riccardi C. A rapid and simple method for measuring thymocyte apoptosis by propidium iodide staining and flow cytometry. J. Immunol. Methods 139(2), 271–279 (1991).Crossref, Medline, CAS, Google Scholar
    • 31 Froidevaux S, Calame-Christe M, Schuhmacher J et al. A gallium-labeled DOTA-α-melanocyte-stimulating hormone analog for PET imaging of melanoma metastases. J. Nucl. Med. 45(1), 116–123 (2004).Medline, CAS, Google Scholar
    • 32 Rijo P, Matias D, Fernandes A, Simões M, Nicolai M, Reis C. Antimicrobial plant extracts encapsulated into polymeric beads for potential application on the skin. Polymers (Basel) 6(2), 479–490 (2014).Crossref, Google Scholar
    • 33 de Oliveira CA, Peres DD, Graziola F et al. Cutaneous biocompatible rutin-loaded gelatin-based nanoparticles increase the SPF of the association of UVA and UVB filters. Eur. J. Pharm. Sci. 81, 1–9 (2015).Crossref, Medline, Google Scholar
    • 34 Knor T, Meholjić-Fetahović A, Mehmedagić A. Stratum corneum hydration and skin surface pH in patients with atopic dermatitis. Acta Dermatovenerol. Croat. 19(4), 242–247 (2011).Medline, CAS, Google Scholar
    • 35 Markovic BD, Vladimirov SM, Cudina OA, Odovic JV, Karljikovic-Rajic KD. A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters. Molecules 17(1), 480–491 (2012).Crossref, Medline, CAS, Google Scholar
    • 36 Yoshida H, Nagaoka A, Kusaka-Kikushima A et al. KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization. Proc. Natl Acad. Sci. 110(14), 5612–5617 (2013).Crossref, Medline, CAS, Google Scholar
    • 37 Jonsson AL, Granqvist A, Elvin J, Johansson ME, Haraldsson B, Nyström J. Effects of melanocortin 1 receptor agonists in experimental nephropathies. PLoS One 9(1), e87816 (2014).Crossref, Medline, Google Scholar
    • 38 Cassard L, Cohen-Solal JFG, Galinha A et al. Modulation of tumor growth by inhibitory Fcγ receptor expressed by human melanoma cells. J. Clin. Invest. 110(10), 1549–1557 (2002).Crossref, Medline, CAS, Google Scholar
    • 39 Nam K, Nam HY, Kim P-H, Kim SW. Paclitaxel-conjugated PEG and arginine-grafted bioreducible poly (disulfide amine) micelles for co-delivery of drug and gene. Biomaterials 33(32), 8122–8130 (2012).Crossref, Medline, CAS, Google Scholar
    • 40 Muhl S, Méndez JM. A review of the preparation of carbon nitride films. Diam. Relat. Mater. 8(10), 1809–1830 (1999).Crossref, CAS, Google Scholar
    • 41 Oliveira CS, de Bock CE, Molloy TJ et al. Macrophage migration inhibitory factor engages PI3K/Akt signalling and is a prognostic factor in metastatic melanoma. BMC Cancer 14(1), 1–14 (2014).Crossref, Medline, Google Scholar
    • 42 Clawson GA, Matters GL, Xin P et al. Macrophage-tumor cell fusions from peripheral blood of melanoma patients. PLoS One 10(8), e0134320 (2015).Crossref, Medline, Google Scholar
    • 43 Haycock JW, Wagner M, Morandini R, Ghanem G, Rennie IG, Mac Neil S. α-Melanocyte-stimulating hormone inhibits NF-κB activation in human melanocytes and melanoma cells. J. Invest. Dermatol. 113(4), 560–566 (1999).Crossref, Medline, CAS, Google Scholar
    • 44 Bichakjian CK, Halpern AC, Johnson TM et al. Guidelines of care for the management of primary cutaneous melanoma. J. Am. Acad. Dermatol. 65(5), 1032–1047 (2011).Crossref, Medline, Google Scholar
    • 45 Antony J, Saikia M, Vinod V et al. DW-F5: A novel formulation against malignant melanoma from Wrightia tinctoria. Sci. Rep. 5, 11107 (2015).Crossref, Medline, CAS, Google Scholar
    • 46 Calvo P, Remunan-Lopez C, Vila-Jato JL, Alonso MJ. Chitosan and chitosan/ethylene oxide-propylene oxide block copolymer nanoparticles as novel carriers for proteins and vaccines. Pharm. Res. [Internet] 14(10), 1431–1436 (1997).Crossref, Medline, CAS, Google Scholar
    • 47 Bennet D, Marimuthu M, Kim S, An J. Dual drug-loaded nanoparticles on self-integrated scaffold for controlled delivery. Int. J. Nanomedicine 7(3399–3419), (2012).Medline, Google Scholar
    • 48 Mizrahy S, Raz SR, Hasgaard M et al. Hyaluronan-coated nanoparticles: the influence of the molecular weight on CD44-hyaluronan interactions and on the immune response. J. Control. Release 156(2), 231–238 (2011).Crossref, Medline, CAS, Google Scholar
    • 49 Liu Y, Sun J, Cao W et al. Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery. Int. J. Pharm. 421(1), 160–169 (2011).Crossref, Medline, CAS, Google Scholar
    • 50 Song S, Chen F, Qi H et al. Multifunctional tumor-targeting nanocarriers based on hyaluronic acid-mediated and pH-sensitive properties for efficient delivery of docetaxel. Pharm. Res. 31(4), 1032–1045 (2014).Crossref, Medline, CAS, Google Scholar
    • 51 Honary S, Zahir F. Effect of zeta potential on the properties of nano-drug delivery systems-a review (Part 2). Trop. J. Pharm. Res. 12(2), 265–273 (2013).Google Scholar
    • 52 Yang X, Li Y, Li M, Zhang L, Feng L, Zhang N. Hyaluronic acid-coated nanostructured lipid carriers for targeting paclitaxel to cancer. Cancer Lett. 334(2), 338–345 (2013).Crossref, Medline, CAS, Google Scholar
    • 53 Ramasamy T, Tran TH, Choi JY et al. Layer-by-layer coated lipid–polymer hybrid nanoparticles designed for use in anticancer drug delivery. Carbohydr. Polym. 102(0), 653–661 (2014).Crossref, Medline, CAS, Google Scholar
    • 54 Hu F-Q, Jiang S-P, Du Y-Z, Yuan H, Ye Y-Q, Zeng S. Preparation and characterization of stearic acid nanostructured lipid carriers by solvent diffusion method in an aqueous system. Colloids Surf. B Biointerfaces 45(0), 167–173 (2005).Crossref, Medline, CAS, Google Scholar
    • 55 Shen H, Shi S, Zhang Z, Gong T, Sun X. Coating Solid lipid nanoparticles with hyaluronic acid enhances antitumor activity against melanoma stem-like cells. Theranostics 5(7), 755 (2015).Crossref, Medline, CAS, Google Scholar
    • 56 Jeong Y-I, Kim DH, Chung C-W et al. Self-assembled nanoparticles of hyaluronic acid/poly(dl-lactide-co-glycolide) block copolymer. Coll. Surf. B Biointerfaces 90(0), 28–35 (2012).Crossref, Medline, CAS, Google Scholar
    • 57 Pohlmann AR, Fonseca FN, Paese K et al. Poly(ε-caprolactone) microcapsules and nanocapsules in drug delivery. Expert Opin. Drug Deliv. 10(5), 623–638 (2013).Crossref, Medline, CAS, Google Scholar
    • 58 Coffin MD, McGinity JW. Biodegradable pseudolatexes: the chemical stability of poly(D,L-Lactide) and poly (ϵ-caprolactone) nanoparticles in aqueous media. Pharm. Res. 9(2), 200–205.Crossref, Medline, Google Scholar
    • 59 Simulescu V, Kalina M, Mondek J, Pekař M. Long-term degradation study of hyaluronic acid in aqueous solutions without protection against microorganisms. Carbohydr. Polym. 137, 664–668 (2016).Crossref, Medline, CAS, Google Scholar
    • 60 Morris GA, Castile J, Smith A, Adams GG, Harding SE. The effect of prolonged storage at different temperatures on the particle size distribution of tripolyphosphate (TPP) – chitosan nanoparticles. Carbohydr. Polym. 84(4), 1430–1434 (2011).Crossref, CAS, Google Scholar
    • 61 das Neves J, Amiji M, Bahia MF, Sarmento B. Assessing the physical–chemical properties and stability of dapivirine-loaded polymeric nanoparticles. Int. J. Pharm. 456(2), 307–314 (2013).Crossref, Medline, CAS, Google Scholar
    • 62 Jain A, Jain SK, Ganesh N, Barve J, Beg AM. Design and development of ligand-appended polysaccharidic nanoparticles for the delivery of oxaliplatin in colorectal cancer. Nanomedicine 6(0), 179–190 (2010).Crossref, Medline, CAS, Google Scholar
    • 63 de la Fuente M, Seijo B, Alonso MJ. Novel hyaluronan-based nanocarriers for transmucosal delivery of macromolecules. Macromol. Biosci. 8(5), 441–450 (2008).Crossref, Medline, CAS, Google Scholar
    • 64 Li Y-Y, Li L, Dong H-Q, Cai X-J, Ren T-B. Pluronic F127 nanomicelles engineered with nuclear localized functionality for targeted drug delivery. Mater. Sci. Eng. C 33(5), 2698–2707 (2013).Crossref, Medline, CAS, Google Scholar
    • 65 Natarajan V, Krithica N, Madhan B, Sehgal PK. Formulation and evaluation of quercetin polycaprolactone microspheres for the treatment of rheumatoid arthritis. J. Pharm. Sci. 100(1), 195–205 (2011).Crossref, Medline, CAS, Google Scholar
    • 66 Go DP, Hung A, Gras SL, O'Connor AJ. Use of a short peptide as a building block in the layer-by-layer assembly of biomolecules on polymeric surfaces. J. Phys. Chem. B 116(3), 1120–1133 (2012).Crossref, Medline, CAS, Google Scholar
    • 67 Contreras LM, de Almeida RFM, Villalaín J, Fedorov A, Prieto M. Interaction of α-melanocyte stimulating hormone with binary phospholipid membranes: structural changes and relevance of phase behavior. Biophys. J. 80(5), 2273–2283 (2001).Crossref, Medline, CAS, Google Scholar
    • 68 Tan CP, Che Man YB. Differential scanning calorimetric analysis of palm oil, palm oil based products and coconut oil: effects of scanning rate variation. Food Chem. 76(1), 89–102 (2002).Crossref, CAS, Google Scholar
    • 69 Giron D. Thermal analysis and calorimetric methods in the characterisation of polymorphs and solvates. Thermochim. Acta 248, 1–59 (1995).Crossref, CAS, Google Scholar
    • 70 de la Ossa DHP, Ligresti A, Gil-Alegre ME et al. Poly-ϵ-caprolactone microspheres as a drug delivery system for cannabinoid administration: development, characterization and in vitro evaluation of their antitumoral efficacy. J. Control. Release 161(3), 927–932 (2012).Crossref, Medline, Google Scholar
    • 71 Šmejkalová D, Nešporová K, Hermannová M et al. Paclitaxel isomerisation in polymeric micelles based on hydrophobized hyaluronic acid. Int. J. Pharm. 466(1–2), 147–155 (2014).Crossref, Medline, CAS, Google Scholar
    • 72 Liu F, Park J-Y, Zhang Y et al. Targeted cancer therapy with novel high drug-loading nanocrystals. J. Pharm. Sci. 99(8), 3542–3551 (2010).Crossref, Medline, CAS, Google Scholar
    • 73 Gao Q, Liang Q, Yu F, Xu J, Zhao Q, Sun B. Synthesis and characterization of novel amphiphilic copolymer stearic acid-coupled F127 nanoparticles for nano-technology based drug delivery system. Coll. Surf. B Bioint. 88(2), 741–748 (2011).Crossref, Medline, CAS, Google Scholar
    • 74 Shi S, Guo Q, Kan B et al. A novel poly(epsilon-caprolactone)-pluronic-poly(epsilon-caprolactone) grafted polyethyleneimine(PCFC-g-PEI), Part 1, synthesis, cytotoxicity, and in vitro transfection study. BMC Biotechnol. 9(1), 65 (2009).Crossref, Medline, Google Scholar
    • 75 Patrícia Dias de Mendonça Rijo. Phytochemical study and biological activities of Diterpenes and derivatives from Plectranthus species. PhD Thesis. University of Lisbon, Portugal (2010).Google Scholar
    • 76 Chang MC, Tanaka J. XPS study for the microstructure development of hydroxyapatite–collagen nanocomposites cross-linked using glutaraldehyde. Biomaterials. 23(18), 3879–3885 (2002).Crossref, Medline, CAS, Google Scholar
    • 77 Selzer D, Abdel-Mottaleb MMA, Hahn T, Schaefer UF, Neumann D. Finite and infinite dosing: difficulties in measurements, evaluations and predictions. Adv. Drug Deliv. Rev. 65(2), 278–294 (2013).Crossref, Medline, CAS, Google Scholar
    • 78 Delehanty JB, Boeneman K, Bradburne CE, Robertson K, Bongard JE, Medintz IL. Peptides for specific intracellular delivery and targeting of nanoparticles: implications for developing nanoparticle-mediated drug delivery. Ther. Deliv. 1(3), 411–433 (2010).Link, CAS, Google Scholar
    • 79 Lu W, Xiong C, Zhang R et al. Receptor-mediated transcytosis: a mechanism for active extravascular transport of nanoparticles in solid tumors. J. Control. Rel. doi:10.1016/j.jconrel.2012.05.014 (2012) (Epub ahead of print).Crossref, Google Scholar
    • 80 Roberts DW, Newton RA, Beaumont KA, Helen Leonard J, Sturm RA. Quantitative analysis of MC1R gene expression in human skin cell cultures. Pigment Cell Res. 19(1), 76–89 (2006).Crossref, Medline, CAS, Google Scholar
    • 81 Tedja R, Lim M, Amal R, Marquis C. Effects of serum adsorption on cellular uptake profile and consequent impact of titanium dioxide nanoparticles on human lung cell lines. ACS Nano 6(5), 4083–4093 (2012).Crossref, Medline, CAS, Google Scholar
    • 82 Arias JL, Reddy LH, Couvreur P. Polymeric nanoparticulate system augmented the anticancer therapeutic efficacy of gemcitabine. J. Drug Target 17(8), 586–598 (2009).Crossref, Medline, CAS, Google Scholar
    • 83 Jeevitha D, Amarnath K. Chitosan/PLA nanoparticles as a novel carrier for the delivery of anthraquinone: synthesis, characterization and in vitro cytotoxicity evaluation. Colloids Surf. B Biointerfaces 101, 126–134 (2013). •• Reports the use of polymeric drug-delivery systems as carriers for phytochemicals with anticancer activity.Crossref, Medline, CAS, Google Scholar
    • 84 de Mattos AC, Altmeyer C, Tominaga T, Khalil NM, Mainardes RM. Polymeric nanoparticles for oral delivery of 5-fluorouracil: formulation optimization, cytotoxicity assay and pre-clinical pharmacokinetics study. Eur. J. Pharm. Sci. 84, 83–91 (2016).Crossref, Medline, CAS, Google Scholar