Abstract 1316: Targeted therapeutic approach for triple negative breast cancer using paramagnetic nanoparticle
Authors: Ali Meser M. , Zhang Li , Bagher Ebadian Hassan , Ewing James R. 
Published: July 2016

Breast cancer (BC) is a spectrum of diseases with distinct molecular alterations accounting for differences in treatment response and outcome. Gene expression profiling defines much of this molecular heterogeneity and has been used to stratify the disease into different molecular subtypes. Triple-negative breast cancer (TNBC) refers to a subtype of breast cancer that is negative for estrogen receptors (ER) and/or progesterone receptors (PR), and lacks HER2 overexpression. Therefore, this subtype of breast cancer lacks the benefits of specific therapies which target these receptors. TNBC has been characterized by an acidic extracellular environment. In human aggressive breast tumors, extracellular pH (pHe) has been measured by microelectrode and the values are in good agreement with the values observed in animal systems i.e. that the pHe is significantly acidic in the range from 6.2 to 7.0. However, tumor intracellular pH is either neutral or alkaline. Interestingly, a similar pH gradient is not observed in normal tissues. Therefore, this acidic extracellular pH (pHe) within tumor tissues can be exploited for targeted delivery of drugs and imaging agents.

Recently, A pH low insertion peptide (pHLIP) derived from the protein bacteriorhodopsin has been found to target tumor acidic pHe. The peptide inserts across cell membranes as an alpha-helix when extracellular pH (pHe) is acidic, but does not form the helix at normal or alkaline pH. Since aggressive TNBC has an acidic environment, the pHLIP will insert into the cancer cell membrane, but the pHLIP will not insert into the cell membranes of normal tissues, providing excellent specificity for targeting TNBC. Our initial study demonstrated the detection of breast tumor in rodent by dendrimer-based paramagnetic nanoparticles nonspecifically. To develop this nanoparticle as a platform, it should easily accommodate targeting ligands for selective localization at the acidic tumor microenvironment and for therapeutic drugs that can be released selectively into TNBC tumor cells. Here, we demonstrate that pHLIP-tagged nanoparticles bind to and are internalized by TNBC cells in in-vitro. Systemic delivery of paramagnetic nanoparticle, Gd-G5-pHLIP (NP-pHLIP) leads to accumulation of the NPs in a flank mouse model of TNBC tumor that are detected by both optical and MR imaging.

Finally, we have conjugated doxorubicin (dox) with pHLIP3-NP via hydrazone bond formation. We have successfully incorporated 20 dox molecules with pHLIP3-NP via a pH-sensitive hydrazone bond as evidenced by maldi-tof analyses. A cohort of 6 mice was treated with pHLIP-NP-dox and a second cohort of 6 mice was treated with vehicle. A solution of 0.04 mmol/kg pHLIP-NP-dox (12mg/kg equivalent dose of dox) was injected through the tail vein catheter at day 8 and 14. We generated T2 maps on day 21′to calculate tumor volume by following our previous reports. We observed a short-term tumor regression by pHLIP-NP-dox infusion.

Citation Format: Meser M. Ali, Li Zhang, Hassan Bagher Ebadian, James R. Ewing. Targeted therapeutic approach for triple negative breast cancer using paramagnetic nanoparticle. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1316.