Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: impact on the treatment of breast cancer
- 577 Downloads
Limiting tumor invasion to the surrounding healthy tissues has proven to be clinically relevant for anticancer treatment options. We have demonstrated that, within a solid tumor, it is possible to achieve such a goal with the same nanoparticle by intracellular and triggered targeted drug delivery to more than one cell population. We have identified the nucleolin receptor in endothelial and cancer cells in tissue samples from breast cancer patients, which enabled the design of a F3-peptide-targeted sterically stabilized pH-sensitive liposome. The clinical potential of such strategy was demonstrated by the successful specific cellular association by breast cancer cells harvested from tumors of patients submitted to mastectomy. In vitro, the nanoparticle targeted the nucleolin receptor on a cell and ligand-specific manner and improved cytotoxicity of doxorubicin (used as a model drug) towards breast cancer and endothelial cells by 177- and 162-fold, respectively, relative to the commercially available non-targeted non-pH-sensitive liposomes. Moreover, active accumulation of F3-targeted pH-sensitive liposomes into human orthotopic tumors, implanted in the mammary fat pad of nude mice, was registered for a time point as short as 4 h, reaching 48% of the injected dose/g of tissue. Twenty-four hours post-injection the accumulation of the dual-targeted pH-sensitive nanoparticle in the tumor tissue was 33-fold higher than the non-targeted non-pH-sensitive counterpart. In mice treated with the developed targeted nanoparticle significant decrease of the tumor viable rim area and microvascular density, as well as limited invasion to surrounding healthy tissues were observed (as opposed to other tested controls), which may increase the probability of tumors falling in the category of “negative margins” with reduced risk of relapse.
KeywordsDrug targeting Triggered drug release Angiogenesis Tumor microenvironment Breast cancer
Vera Moura was the recipient of a fellowship from the Portuguese Foundation for Science and Technology (FCT) (ref.: SFRH/BD/21648/2005). The work was supported by a Portuguese grant from FCT, “Programa Operacional Ciência, Tecnologia, Inovação” (POCTI) and “Fundo Europeu de Desenvolvimento Regional” (FEDER) (ref.: POCI/SAU-OBS/57831/2004) and Portugal–Spain capacitation program in nanoscience and nanotechnology (ref.: NANO/NMed-AT/0042/2007).
- 1.WHO (2009) Fact sheet N°297Google Scholar
- 4.Stuelten CH, Busch JI, Tang B, Flanders KC, Oshima A, Sutton E, Karpova TS, Roberts AB, Wakefield LM, Niederhuber JE (2010) Transient tumor-fibroblast interactions increase tumor cell malignancy by a TGF-Beta mediated mechanism in a mouse xenograft model of breast cancer. PLoS One 5(3):e9832PubMedCrossRefGoogle Scholar
- 11.Kleinman HK, Weeks BS, Cannon FB, Sweeney TM, Sephel GC, Clement B, Zain M, Olson MO, Jucker M, Burrous BA (1991) Identification of a 110-kDa nonintegrin cell surface laminin-binding protein which recognizes an A chain neurite-promoting peptide. Arch Biochem Biophys 290(2):320–325PubMedCrossRefGoogle Scholar
- 17.Marchio S, Lahdenranta J, Schlingemann RO, Valdembri D, Wesseling P, Arap MA, Hajitou A, Ozawa MG, Trepel M, Giordano RJ, Nanus DM, Dijkman HB, Oosterwijk E, Sidman RL, Cooper MD, Bussolino F, Pasqualini R, Arap W (2004) Aminopeptidase A is a functional target in angiogenic blood vessels. Cancer Cell 5(2):151–162PubMedCrossRefGoogle Scholar
- 28.Lengyel E, Prechtel D, Resau JH, Gauger K, Welk A, Lindemann K, Salanti G, Richter T, Knudsen B, Vande Woude GF, Harbeck N (2005) C-Met overexpression in node-positive breast cancer identifies patients with poor clinical outcome independent of Her2/neu. Int J Cancer 113(4):678–682PubMedCrossRefGoogle Scholar
- 34.Daenen LG, Shaked Y, Man S, Xu P, Voest EE, Hoffman RM, Chaplin DJ, Kerbel RS (2009) Low-dose metronomic cyclophosphamide combined with vascular disrupting therapy induces potent antitumor activity in preclinical human tumor xenograft models. Mol Cancer Ther 8(10):2872–2881PubMedCrossRefGoogle Scholar
- 36.Meric F, Mirza NQ, Vlastos G, Buchholz TA, Kuerer HM, Babiera GV, Singletary SE, Ross MI, Ames FC, Feig BW, Krishnamurthy S, Perkins GH, McNeese MD, Strom EA, Valero V, Hunt KK (2003) Positive surgical margins and ipsilateral breast tumor recurrence predict disease-specific survival after breast-conserving therapy. Cancer 97(4):926–933PubMedCrossRefGoogle Scholar