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Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: impact on the treatment of breast cancer

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Abstract

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.

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Acknowledgments

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).

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Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517, Coimbra, Portugal

    Vera Moura, Maria C. Pedroso de Lima, Sérgio Simões & João N. Moreira

  2. Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Vera Moura, Sérgio Simões & João N. Moreira

  3. Portuguese Institute of Oncology FG, EPE, Coimbra, Portugal

    Manuela Lacerda & Paulo Figueiredo

  4. Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal

    Maria L. Corvo & Maria E. M. Cruz

  5. Department of Biochemistry, Faculty of Medicine of the University of Porto, Porto, Portugal

    Raquel Soares

  6. Department of Life Sciences, University of Coimbra, Coimbra, Portugal

    Maria C. Pedroso de Lima

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  1. Vera Moura
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Correspondence to João N. Moreira.

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Moura, V., Lacerda, M., Figueiredo, P. et al. Targeted and intracellular triggered delivery of therapeutics to cancer cells and the tumor microenvironment: impact on the treatment of breast cancer. Breast Cancer Res Treat 133, 61–73 (2012). https://doi.org/10.1007/s10549-011-1688-7

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  • DOI: https://doi.org/10.1007/s10549-011-1688-7

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