Uptake by breast carcinoma of a lipidic nanoemulsion after intralesional injection into the patients: A new strategy for neoadjuvant chemotherapy S. Mendes a , S.R. Graziani a,b , T.S. Vitório a,d , A.F. Padoveze a , R. Hegg b , S.P. Bydlowski c , R.C. Maranhão a,d, ⁎ a Lipid Metabolism Laboratory of the Heart Institute (InCor), University of São Paulo, São Paulo, Brazil b Gynecology Department, University of São Paulo, São Paulo, Brazil c Laboratory of Genetics and Molecular Hematology (LIM31) of the Medical School Hospital, University of São Paulo, São Paulo, Brazil d Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil abstract article info Article history: Received 25 August 2008 Available online 5 December 2008 Keywords: Breast intralesional injection Breast cancer treatment Lipidic nanoemulsion Nanoparticles Low-density lipoprotein receptors Objective. Previously we showed that after intravenous injection a lipidic nanoemulsion concentrates in breast carcinoma tissue and other solid tumors and may carry drugs directed against neoplastic tissues. Use of the nanoemulsion decreases toxicity of the chemotherapeutic agents without decreasing the anticancer action. Currently, the hypothesis was tested whether the nanoemulsion concentrates in breast carcinoma tissue after locoregional injection. Methods. Three different techniques of injection of the nanoemulsion were tested in patients scheduled for surgical treatment: G1 (n =4) into the mammary tissue 5 cm away from the tumor; G2 (n =4) into the peritumoral mammary tissue; G3 (n = 6) into the tumoral tissue. The nanoemulsion labeled with radioactive cholesteryl oleate was injected 12 h before surgery; plasma decay of the label was determined from blood samples collected over 24 h and the tissue fragments excised during the surgery were analyzed for radioactivity uptake. Results. Among the three nanoemulsion injection techniques, G3 showed the greatest uptake (data expressed in c.p.m/g of tissue) by the tumor (44,769 ± 54,749) and by the lymph node (2356 ± 2966), as well as the greatest concentration in tumor compared to normal tissue (844±1673). In G1 and G2, uptakes were, respectively, tumor: 60 ±71 and 843 ±1526; lymph node: 263 ±375 and 102±74; normal tissue: 139 ±102 and 217 ± 413. Conclusions. Therefore, with intralesional injection of the nanoemulsion, a great concentration effect can be achieved. This injection technique may be thus a promising approach for drug-targeting in neoadjuvant chemotherapy in breast cancer treatment. © 2008 Published by Elsevier Inc. Introduction In previous studies, we showed that a cholesterol-rich nanoemul- sion is taken up by the cells by the low-density lipoprotein (LDL) receptors [1]. The nanoparticle is composed of a core of cholesterol esters and residual amounts of triglycerides surrounded by a monolayer of phosphatidylcholine with free cholesterol. It is produced without proteins, but in contact with the plasma it acquires apolipoproteins (apo) E and other apos [2,3]. Apo E endows the nanoemulsion with the ability of being recognized and taken-up by the LDL receptors. Because LDL receptors are upregulated in several neoplastic cells [4–6], after injection into the blood stream the nanoemulsion concentrates in the neoplastic tissues and may carry drugs directly against those tissues. This drug-targeting strategy may decrease the toxicity and increase the antitumoral action in cancer chemotherapy and this was indeed confirmed in animal models, in which the association of derivatized forms of etoposide or paclitaxel to the nanoemulsion were tested [7,8]. In pilot clinical trials enrolling small number of patients with advanced cancer, we showed that association of both drugs to the lipidic nanoemulsion markedly reduced their toxicity. This effect was also obtained in cancer patients treated with the nanoemulsion associated with carmustine [9,10]. The intravenous injection of the nanoemulsion may produce a concentration of the drug in the tumor as high as fivefold in breast cancer [11] and tenfold in ovarian carcinoma [12], compared with the uptake of the normal organ tissue. The nanoemulsion system furnishes not only a drug targeting instrument but it facilitates the delivery into the cells of the chemotherapeutic agents by means of the LDL receptor mediated endocytosis [1]. The local or locoregional injection can be an interesting strategy of drug administration in cancer chemotherapy that is, however, limited by damage to the surrounding local tissues or by difficulty of the drugs Gynecologic Oncology 112 (2009) 400–404 ⁎ Corresponding author. Instituto do Coração (InCor) do Hospital das Clínicas FMUSP, Laboratório de Metabolismo de Lípides. Av. Dr. Enéas de Carvalho Aguiar, 44, 1° subsolo, São Paulo, SP, 05403-000, Brazil. Fax: +55 11 3069 5574. E-mail address: ramarans@usp.br (R.C. Maranhão). 0090-8258/$ – see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.ygyno.2008.10.018 Contents lists available at ScienceDirect Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno