Synthesis and Biofunctionalization of Novel Composite Nanocarriers for Targeted Detection and Treatment of Malignant Cells

At present, mammary carcinoma is the second most common type of malignant tumor in adult women after lung cancer, as more than one million women are diagnosed with breast cancer every year. Despite advances in diagnosis and treatment, which have resulted in a decrease in mortality in this decade, breast cancer remains a major public health problem. Nevertheless, the heterogeneity of human breast cancer in terms of genetic features, molecular profiles and clinical behavior represents a constraint obstructing the discovery of a solution to the disease. It is currently considered that the chances of success of therapy may increase if the tumor cells are selectively removed before they can evolve to their mature stages up to metastases production. Recently, to overcome these hurdles, monoclonal antibodies (mAb) coupled within nanomaterials have been designed to improve tissue targeting and penetration in early diagnosis of breast cancer. Among the molecular targets considered for the treatment of breast cancer cells so far, my primary goal has been focused on two examples involving overexpression and/or gene amplification of epidermal breast cancer receptors such as “Human Epidermal growth factor Receptor 2” (HER2), transferrin receptor (TfR) and urokinase plasminogen activator receptor (uPAR) proteins. In the first study spherical silica nanoparticles (SiNPs) have been conjugated with the anti-HER2 scFv800E6 antibody, by both oriented protein ligation and unoriented protein ligation. The targeting efficiency of nanocomplexes have been evaluated and compared with free scFv and the whole monoclonal antibody Trastuzumab (Tz) in HER2 positive breast cancer cells (MCF7). In a parallel study, we adopted the same concept optimizing the conjugation through an oriented ligation of Transferrin protein onto fluorescent SiNPs, for the selective targeting of TfR in A549 a lung cancer cell model. In a second project, multifunctional iron oxide nanoparticles (MNPs), which combine magnetic properties and fluorescence emission have been functionalized with a bimodular genetic fusion protein, called HALO–U11, comprising a small peptide of 11 amino acids (U11) that has a high affinity for uPAR receptor and the HALO protein as a nanomaterial capture module. The targeting efficiency of this system have been compared in both uPAR(+) and uPAR(−) cell lines. In parallel to cancer diagnosis accomplished with inorganic nanomaterials, my attention turned to cancer therapy. According to this purpose, it has been developed an organic nanoformulation for drug delivery of potentially new therapeutic compounds for breast cancer. Indeed, poly(lactide-co-glycolyde) nanoparticles (PLGA NPs), the most studied polymer as tool for several drugs against different kinds of malignancies, have been developed by a single-emulsion process, with the aim to encapsulate natural and artificial curcuminoids; these molecules have been shown to possess a wide range of pharmacological activities, including anti-inflammatory, antioxidant and anticancer effects. PLGA NPs have exhibited a curcumin release following a Fickian-law diffusion over 10 days in vitro; later on, it has been investigated the possibility to study the intracellular degradation of PLGA NPs associated with a specific G2/M blocking effect on MCF7 breast cancer cells caused by curcumin release in the cytoplasm, which provided direct evidence on the mechanism of action of this nanoformulation. In conclusion, able to provide both accurate diagnosis and effective therapy of breast cancer, novel hybrid nanostructures have being developed intensely. The goal of this approach is to obtain targeted multimodal nanoparticles capable of being vectors of therapy, a source of signals for diagnosis and monitoring of endogenous response at the same time.