Highly Efficient Theranostic Nano Vehicles with a Dual Therapeutic Approach Against Triple-Negative Breast Cancer

Up to date, triple-negative breast cancer (TNBC) is responsible for more than 15 % of new breast cancer cases per year. A destructive and difficult-to-treat cancer lacking expression of common docking sites hormone-sensitive breast cancers display such progesterone or estrogen receptors (PgR, ER) as well as human epidermal growth factor receptor (HEGFR). Except missing expression of targeting receptors, TNBC shows aggressive heterogeneous tumor biology with a high risk of reoccurrence and metastasis and, therefore, therapeutic options for patients are limited.<br/>In this study, a targeted dual-purpose therapeutic nanocarrier is developed by integrating complementary functionalities and payloads (doxorubicin, radionuclides ⁶⁸Ga/¹⁷⁷Lu) into one nanocarrier through covalent conjugation strategies. The nanocarriers, [⁶⁸Ga]Ga-DOTA-FA and [¹⁷⁷Lu]Lu-DOTA-FA demonstrated an outstanding radiochemical yield of &gt; 98 % showing successful incorporation of radionuclides to DOTA cavity. Moreover, radiolabeled nanocarrier exhibited excellent stability in PBS buffer and human serum during 3 h (⁶⁸Ga) and 120 h (¹⁷⁷Lu). In addition, the labeled FA-DOTA@mSiO₂ exhibited a favourable partition coefficient (log P) of -3.29 ± 0.08, suggesting highly hydrophilic carriers. In vitro studies using 3 different TNBC cell lines with FA-DOTA@mSiO₂ carriers demonstrated a significant cell internalization suggesting specific targeting of folate receptors in TNBC cells. Interestingly, FA-capped nanocarrier revealed a significant time-dependent cell uptake after radiolabeling with ¹⁷⁷Lu in SUM149PT (33 %) MDA-MB-231 (9%), BT20 (28%) compared to nanocarrier without FA. Apoptosis assays showed combined delivery of radiations and DOX-induced significant cell death to TNBC cells earlier at different time points. Our data suggest that dual-functions nanocarriers has great potential in targeted delivery of radiations and drug doses for TNBC tumor treatment and points out further studies to evaluate its preclinical therapeutic efficacy.