Abstract P1-10-11: Multivalent exposure of trastuzumab on iron oxide nanoparticles enhances antitumor activity and weakens drug resistance in HER2+ breast cancer cells

Abstract

Abstract Background: The identification of new strategies aimed to optimize the treatment of breast cancer and its metastases represents a great technical and medical challenge. Target-specific therapies, such as Trastuzumab (TZ), have revolutionized the clinical scenario in certain subsets of cancer. However, the huge variability in response to therapy and the frequent onset of drug resistance in patients still hamper the therapeutic success. Antibody-conjugated nanoparticles may combine specific recognition of tumor cells with the capability to act as innovative reservoir of active drugs. Here, multivalent TZ-conjugated colloidal nanoparticles were developed as target-specific and biologically active nanosystem to enhance the therapeutic potential toward HER2+ breast cancer. Methods: Iron oxide nanoparticles conjugated with multiple half chains of TZ have been developed and tested in different HER2+ breast cancer cell lines, in comparison to free TZ or untargeted nanoparticles. Active targeting and specificity toward HER2 receptor was assessed by flow cytometry and confocal microscopy. Cellular uptake of nanoparticles and HER2 endocytosis were followed by electron or confocal microscopy. Direct anticancer efficacy was assessed by incubation of free or nanoformulated TZ on sensitive breast cancer cells, and analysis of cell viability, cell cycle, and expression of p27kip1. Finally, nanoparticles were tested on TZ-resistant breast cancer cell lines for capability of re-sensitization. Results: TZ-conjugated nanoparticles showed specific targeting of HER2, with induction of site-specific phosphorylation in the catalytic domain of the receptor and cellular uptake by endocytosis. Treatment with TZ-conjugated nanoparticles dramatically decreased cancer cell viability, by significantly improving the antitumor activity of TZ. This effect was independent from the ADCC mechanism, and associated with marked induction of p27kip1 expression and cell cycle arrest in G1 phase in TZ-sensitive SKBR-3 cells. TZ-conjugated nanoparticles also affected viability of breast cancer cells insensitive to TZ, further confirming enhanced potential of the nanoformulation and suggesting interference with some mechanisms of resistance. Conclusions: Our results provide evidence that multivalent exposure of TZ half chain on iron oxide nanoparticles affords enhanced antitumor potential and target-specific activity in HER2+ breast cancer cells. Powerful inhibition of HER2 signaling by TZ-conjugated nanoparticles could favor responsiveness of drug resistant cells, thus suggesting novel therapeutic strategies to overcome resistance. Citation Format: Truffi M, Monieri M, Sorrentino L, Mazzucchelli S, Colombo M, Pandolfi L, Prosperi D, Corsi F. Multivalent exposure of trastuzumab on iron oxide nanoparticles enhances antitumor activity and weakens drug resistance in HER2+ breast cancer cells [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-11.