Biomimetic cancer cell membrane-wrapped nanoparticles for dual photothermal therapy and photoacoustic imaging of triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer diagnoses and is the most aggressive and difficult-to-treat subtype of breast cancer due to the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)—key targets for existing hormonal and targeted therapies. As a result, the standard treatment for TNBC remains non-specific chemotherapy, often combined with surgery and/or radiation. However, these treatments have limitations, resulting in high rates of recurrence, metastasis, and poor prognosis. There is an urgent need for more effective, tumor-targeted therapeutic and diagnostic strategies that improve patient outcomes while minimizing systemic side effects. ☐ Photothermal therapy (PTT) is a promising non-invasive cancer treatment in which light-sensitive nanoparticles (NPs) such as gold nanoshells (NS) are injected intravenously and once they arrive at the tumor site an externally applied laser is used to irradiate the NPs, causing them to convert the light energy into heat to thermally ablate the tumor. Excitingly, PTT mediated by NS coated with the passivating agent poly(ethylene glycol) (PEG) (PEG-NS) has entered human clinical trials for prostate and head & neck cancers with promising results reported, warranting investigation of NS-mediated PTT as a viable treatment for TNBC. ☐ The success of PTT relies on sufficient nanoparticle accumulation in tumors after systemic administration. Traditionally, NS and other light-responsive NPs are coated with PEG to minimize protein opsonization and extend circulation in the blood, but PEG coatings do not enable specific targeting of diseased cells, and they can cause an undesirable immune response that triggers the accelerated blood clearance phenomenon, in which second doses of PEG-coated NPs are rapidly cleared from circulation. NS and other light-responsive NPs have also been coated with molecules such as antibodies, peptides, or aptamers to enable cancer cell-specific targeting, but these approaches have only modestly improved delivery compared to PEG-coated NPs. There remains a critical need for surface modifications that can elevate delivery to tumors while minimizing delivery to non-targeted sites. ☐ Recent studies by the Day Lab and others have shown that coating NPs with plasma membranes derived from cancer cells can enable immune evasion and improve the NPs’ tumor-targeting ability by replicating the cancer cell exterior on the surface of the NP. By transferring “marker of self” and “cell adhesion” proteins from the cell onto the NP surface, improved biointerfacing is achieved. This dissertation demonstrates that TNBC cell membrane-wrapped nanoshells (MWNS) are a promising tool to improve PTT of TNBC because they achieve higher levels of tumor delivery compared to PEG-NS. This thesis also demonstrates that MWNS enable enhanced detection of TNBC cells and tumors through photoacoustic (PA) imaging compared to PEG-NS. ☐ Chapter 1 provides an overview of cancer, and breast cancer with a focus on TNBC, discusses current treatment options and the advantages of NP-mediated PTT, and introduces the concepts that inspired the development of the MWNS platform presented in this dissertation. Chapter 2 describes the materials and methods used to synthesize and characterize the physicochemical and optical properties of MWNS. Chapter 3 presents the results and discussion related to MWNS characterization and demonstrates that wrapping NS in TNBC membranes does not alter their optical properties. Further, Chapter 3 shows that MWNS have excellent cytocompatibility, are stable in physiologic solutions, and can preferentially target homotypic cancer cells in vitro to yield more effective photothermal cell death than PEG-NS. Chapter 4 evaluates the photoacoustic (PA) imaging properties of MWNS in vitro and examines their in vivo biodistribution, tumor accumulation, and PA imaging potential in mice bearing orthotopic TNBC tumors after intravenous administration. Notably, MWNS exhibited greater tumor accumulation than PEG-NS, resulting in higher PA signal within TNBC tumors. Chapter 5 describes studies evaluating the anti-tumor effect of MWNS-mediated PTT, and shows this treatment can slow primary tumor growth and reduce lung metastasis of TNBC in vivo more effectively than PTT mediated by PEG-NS. Finally, Chapter 6 outlines the overall impact of this work and offers perspectives on future directions for this technology. ☐ In summary, this dissertation introduces a novel, biomimetic NP platform for targeted imaging and therapy of TNBC. This MWNS system represents a significant step toward more effective, personalized, and minimally invasive treatments for TNBC, which may ultimately be adapted for other hard-to-treat diseases. Future directions include the exploration of alternative membrane sources, combination with other entities such as immunotherapies to maximize patients’ successful outcomes, and, in the longer term, translation into clinical trials or testing in alternative disease models. The promising results presented here lay the groundwork for the continued development of multifunctional, biomimetic, photoresponsive nanoparticles in precision medicine.