Synthesis and In Vitro Efficacy of MMP9-Activated NanoDendrons

Samuelson, Lynn E.; Scherer, Randy L.; Matrisian, Lynn M.; McIntyre, J. Oliver; Bornhop, Darryl J.

doi:10.1021/mp4002206

Cited by 21 publications

(21 citation statements)

References 41 publications

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“…Using a design based on our proteolytic beacons (McIntyre et al, 2004; McIntyre and Matrisian, 2009; McIntyre et al, 2010), we recently demonstrated a PXL prodrug that is not toxic to tumor cells in vitro until activated by MMP9 (Samuelson et al, 2013). In these studies, we report the synthesis of a similar MMP9-activated PXL prodrug, ND PXL , constructed on a clickable NanoDendron (ND) scaffold and an analogous proteolytic beacon, ND PB .…”

Section: Introductionmentioning

confidence: 99%

New tools for the quantitative assessment of prodrug delivery and neurotoxicity

et al. 2015

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Systemic off-target toxicities, including neurotoxicity, are prevalent side effects in cancer patients treated with a number of otherwise highly efficacious anticancer drugs. In the current study, we have: 1) developed a new analytical metric for the in vivo preclinical assessment of systemic toxicities/neurotoxicity of new drugs and delivery systems; and 2) evaluated, in mice, the in vivo efficacy and toxicity of a versatile and modular NanoDendron (ND) drug delivery and imaging platform that we recently developed. Our paclitaxel-carrying ND prodrug, NDPXL, is activated following proteolytic cleavage by MMP9, resulting in localized cytotoxic chemotherapy. Using click chemistry, we combined NDPXL with a traceable beacon, NDPB, yielding NDPXL-NDPB that functions as a theranostic compound. In vivo fluorescence FRET imaging of this theranostic platform was used to confirm localized delivery to tumors and to assess the efficiency of drug delivery to tumors, achieving 25-30% activation in the tumors of an immunocompetent mouse model of breast cancer. In this model, ND-drug exhibited anti-tumor efficacy comparable to nab-paclitaxel, a clinical formulation. In addition, we combined neurobehavioral metrics of nociception and sensorimotor performance of individual mice to develop a novel composite toxicity score that reveals and quantifies peripheral neurotoxicity, a debilitating long-term systemic toxicity of paclitaxel therapy. Importantly, mice treated with nab-paclitaxel developed changes in behavioral metrics with significantly higher toxicity scores indicative of peripheral neuropathy, while mice treated with NDPXL showed no significant changes in behavioral responses or toxicity score. Our ND formulation was designed to be readily adaptable to incorporate different drugs, imaging modalities and/or targeting motifs. This formulation has significant potential for preclinical and clinical tools across multiple disease states. The studies presented here report a novel toxicity score for assessing peripheral neuropathy and demonstrate that our targeted, theranostic NDs are safe and effective, providing localized tumor delivery of a chemotherapeutic and with reduced common neurotoxic side-effects.

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Section: Introductionmentioning

confidence: 99%

New tools for the quantitative assessment of prodrug delivery and neurotoxicity

et al. 2015

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“…This study describes a self-reporting nanomedicine that not only delivers chemotherapy or immunotherapy to the tumor but also reports back on its efficacy in real time, thereby identifying responders and nonresponders early on. a therapeutic that was activated inside the tumor by matrix metalloproteinase enzymes and thereby reduced off-target toxicity (29).…”

Section: Significancementioning

confidence: 99%

Reporter nanoparticle that monitors its anticancer efficacy in real time

Kulkarni

Rao

Natarajan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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 ...

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“…For example, patients treated with doxorubicin (DOX) and paclitaxel (PXL) can develop cardiotoxicity and peripheral neuropathy. To circumvent this, the conjugation of DOX and PXL to nanodendrons to generate prodrugs can potentially mitigate these systemic side effects [101]. Linking the DOX and PXL nanondendrons with an MMP-9 selective amino acid sequence allows for the activation of the prodrugs by MMP-9 overexpressing cancers.…”

Section: New Tools To Image Mmp Activity In Vivomentioning

confidence: 99%

New approaches to selectively target cancer-associated matrix metalloproteinase activity

Tauro

McGuire

Lynch

2014

Cancer Metastasis Rev

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Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.

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Synthesis and In Vitro Efficacy of MMP9-Activated NanoDendrons

Cited by 21 publications

References 41 publications

New tools for the quantitative assessment of prodrug delivery and neurotoxicity

New tools for the quantitative assessment of prodrug delivery and neurotoxicity

Reporter nanoparticle that monitors its anticancer efficacy in real time

New approaches to selectively target cancer-associated matrix metalloproteinase activity

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