Reporter nanoparticle that monitors its anticancer efficacy in real time

Abstract

The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.T he failure of anticancer therapy is a major cause of mortality (1). Although the current dogma underlying resistance is based on the Darwinian selection of mutations acquired over time under chemotherapy pressure, emerging evidence indicates that anticancer drugs can be rendered ineffective early on by intrinsic or adaptive resistance as a function of tumor heterogeneity (2-4). For example, response rates to first-line chemotherapy treatments in metastatic breast cancer patients range from a dismal 30% to 70%, and patients with disease progression need to be switched to a different drug (5). Similarly, about 40-60% of patients with a wild-type KRAS do not respond to cetuximab (6). The ability to detect early whether a treatment is working or not and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life (7,8).Currently, tumor response to therapy is determined using techniques for direct anatomical measurements, such as computed tomography (CT) and magnetic resonance imaging, or indirectly using positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) to quantify metabolic activity. However, these techniques lack the sensitivity or specificity to enable very early response assessment, and often, clinicopathological and metabolic readouts can be discordant (5, 9, 10). In the case of immunotherapy, for example, a productive immune response (T cell infiltration) and the unimpeded growth of the tumor will both be manifest as progression on the conventional ...

Nanoparticle Design Strategies for Effective Cancer Immunotherapy

“…In vivo studies have tested a range of particle sizes, mostly less than 300 nm, and particles with both positive and negative zeta potentials for various applications. Material composition and surface modifications have been shown to contribute significantly in selective targeting, efficient delivery and active stimulation of immune system targets [35, 41, 43-66]. Thus, these investigations, including a wide array of nanoparticles for cancer immunotherapy, substantiate the employment of nanocarriers for efficacious cancer immunotherapies.…”

“…For non-specific immunotherapy, the enhanced delivery of certain adjuvants, such as cytokines, can be achieved with the help of nanoparticles to boost the immune response in conjunction with other cancer immunotherapies. Nanoparticles also benefit from theranostic applications including delivery of imaging agents along with the therapeutic moieties to diagnose and track the treatment [41, 42]. …”

Isolating the sources of heterogeneity in nanoparticle-cell interactions

“…Uncovering the biological and physical mechanisms that impact the ability of specific cells to associate with, and subsequently internalize, nanoparticles is necessary for informed nanoparticle design (1,2,7). The ability to reliably deliver nanoparticles to a target cell population such that the nanoparticles are rapidly internalized has the potential to transform disease treatment and diagnosis (34)(35)(36). However, the journey between nanoparticle creation and cellular internalisation is convoluted, and involves a multitude of intertwined biological, physical and chemical processes (1-4, 7).…”

A Nitric Oxide (NO) Nanoreporter for Noninvasive Real‐Time Imaging of Macrophage Immunotherapy

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