TREAT U participation in the American Association for Cancer Research Annual Meeting 2013

A novel targeted triggered release nanoparticle against cancer cells of diverse histological origin

Authors: Vera Moura (a), Manuela Lacerda (d), Paulo Figueiredo (d), Maria L. Corvo (e), Maria E. M. Cruz (e), Raquel Soares (f), Maria C. Pedroso de Lima (b,g), Sérgio Simões (a,b,c), João N. Moreira (b,c)
Authors’affiliations: aTreat U, Lda., Portugal, bCenter for Neuroscience and Cell Biology, University of Coimbra, Portugal, cFaculty of Pharmacy, University of Coimbra, Portugal, dPortuguese Institute of Oncology FG, EPE, Portugal, eResearch Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Portugal, fDepartment of Biochemistry, Faculty of Medicine of the University of Porto, Portugal, gDepartment of Life Sciences, University of Coimbra, Portugal.

 

Abstract

The paradigm of cancer treatment has changed substantially over the last decade. The discovery of new therapeutic targets within the tumor cell and the recognition of the interdependence with the tumor microenvironment have been the basis of such changes. However, no common ground was yet found for the treatment of cancer within its diverse histological origin. Conventional therapy against human canc­er, relying on the use of drugs that do not differentiate between cancer and normal cells, is progressively giving room to novel therapeutic strategies. Specificity became mandatory for treatment effectiveness and target selection one of the main priorities. In this scenario, delivery systems rise as promising approaches, for the reason they can improve pharmacokinetic features of anticancer drugs and efficiently address a particular payload to a selected target, namely through exploitation of high specificity and affinity between cell-surface receptors and targeting ligands coupled at their surface.

We evidence the overexpression of a target cell surface receptor (nucleolin) in several cancer cell lines of diverse histological origins: breast (hormone-dependent and triple negative subtypes), colon, prostate and small cell and non-small cell lung cancer. We demonstrate the ability of the nucleolin receptor to specifically internalize a F3-targeted sterically stabilized lipid-based formulation. Moreover, we show that the unique combination of targeting specificity and intracellular triggered release of a therapeutic agent, doxorubicin, results in enhanced cytotoxic activity in those specific cell lines, when compared to the non-targeted counterpart.

Active accumulation of the targeted nanoparticle 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 accumulation in the tumor tissue was 33-fold higher than the non-targeted counterpart. In mice treated with the targeted nanoparticle containing doxorubicin, 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). Moreover, 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.

Overall, we provide evidence of a nanoparticle with specificity to cancer cells of diverse histological origins and proven therapeutic efficacy in an animal model of breast cancer, which may be a breakthrough in the development of anticancer therapies, especially when considering cancer cell heterogeneity.