Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin.

Dominick Salerno,Stavroula Sofou

doi:10.3390/ph14101035

Abstract

Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles.

Highlights

Breast cancer is the most commonly diagnosed cancer in women [1]
Some triple-negative breast cancers (TNBC) tumors may likely be driven by chemotherapy-resistant cells that may be the reason behind the limited response to neoadjuvant chemotherapy [3]
We demonstrated that the presentation of a cationic charge on an undulating PEG chain significantly reduced the NP interactions with cancer cells, limiting their cell internalization, but it retained measurable adhesion to the tumors’ extracellular matrix (ECM) [16,17]

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer in women [1]. Approximately10–15% of all breast cancers are defined as triple-negative breast cancers (TNBC), with known cell surface molecular markers (estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)) not being highly expressed. Pharmaceuticals 2021, 14, 1035 efficacy in the clinic since cancer cells that do not get exposed to lethal levels of therapeutic agents may not be killed [4]. In advanced (stage II–III) TNBC, neoadjuvant chemotherapy, followed by surgery and by additional chemotherapy, aims to improve the pathological complete response (pCR) in the breast and axilla, which is considered a reliable prognostic factor in terms of recurrence and survival. Several ongoing clinical trials evaluate the efficacy of a variety of neoadjuvant treatment schemes to improve the pCR. These schemes combine therapeutics that act in different ways: either by killing the cancer cells, stopping their division, and/or limiting their ability to spread.

Methods

Results

Conclusion