Niharika Choudhury

Introduction. Triple Negative Breast Cancer (TNBC) comprises 15-20% of all breast cancers and is considered the most aggressive phenotype.^1,2 It is diagnosis of exclusion, characterized by the loss of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu).^1,2 This genomic instability leads to an increased rate of metastasis with an observed median survival time of 13.3 months.^1,2 Standard treatment of TNBC consists of surgery, chemotherapy, and radiotherapy, which observe significant off-target cytotoxic effects.^2,3 It is thus imperative to identify TNBC subtypes to provide molecular target-based therapy. Nanoparticles offer a unique solution in optimized TNBC treatment by serving as drug delivery vehicles to enhance current therapies while minimizing side effects, optimizing PK/PD properties, and potentially accounting for metastases.^3,4 Methods and Results. Nanoparticles can be designed with a high degree of control over biodistribution, delivery mechanism, and packaged therapeutic type. To deliver the mainstay chemotherapeutic paclitaxel to EGFR+ TNBC patients, a nanodiamond nanocomposite is constructed to conjugate with paclitaxel and cetuximab, an anti-EGFR antibody.⁵ This induces mitotic catastrophe, apoptosis, and tumor inhibition without significant off-target effects.⁵ However, immune evasion is often observed with TNBC development. Nanofluidic drug-eluding seeds with silicon-microfabricated membranes are designed to deliver immunostimulatory antibodies targeting CD40, a co-stimulatory protein, in a sustained manner to stimulate anti-tumor immune activity locally and potentially systemically.⁶ Chitosan guanidinate “nanobomb” nanoparticles offer a solution for siRNA-based therapies, stabilizing siPOLR2A to enhance the reduction of growth of hemizygous POLR2A/TP53 TNBC tumors while also allowing for pH-dependent CO2 release for lysosomal escape.⁷ To further allow for a theranostic approach, a cationic lipid nanocarrier is decorated with siRNA against Bcl-2 and PKC-l, aptamers for EGFR-targeting, and quantum dots for simultaneous fluorescence imaging.⁸ These particles targeted TNBC cells and inhibited the proliferation and metastasis of tumors in murine models.⁸ Finally, to address the cytotoxicites associated with systemic ionizing radiation therapy, triangular silver-based nanoparticles are designed for co-local heat delivery in hyperthermic sensitization of TNBC cells.⁹ This reduces the required dose and frequency of IR treatment, as observed in murine models.⁹ Conclusions. Nanodrug delivery systems offer a promising solution for targeted TNBC treatment, as they can be designed to localize to the tumor, escape immune degradation, and increase delivery of traditional therapies. Outstanding challenges include clinical relevance and the heterogeneity of TNBC tumors. However, the possibility of integrating various modes of control allows for nanoparticles to be dynamic yet effective solutions in TNBC treatment.

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