New tools for the quantitative assessment of prodrug delivery and neurotoxicity

Abstract

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.

Fn14-Directed DART Nanoparticles Selectively Target Neoplastic Cells in Preclinical Models of Triple-Negative Breast Cancer Brain Metastasis

“…Importantly, a comparison of NP biodistribution in major organs 96 h after administration did not reveal aberrant accumulation of Cy5-PP-IT4 NPs in non-clearance organs, whereas Cy5-Abraxane exhibited significant accumulation in the lungs (Figure S3D). This was anticipated by the >150 nm diameter of Cy5-Abraxane, but it has also been reported by others to occur with unlabeled Abraxane, underscoring the potential for this formulation to induce off-target respiratory system effects . Indeed, drug-induced lung injury upon Abraxane administration in humans is not rare and may be avoided with paclitaxel delivery via polymeric NP formulations like our DART NPs.…”

Secreted Matrix Metalloproteinase-9 of Proliferating Smooth Muscle Cells as a Trigger for Drug Release from Stent Surface Polymers in Coronary Arteries

“…Both peptides have been previously reported as MMP-9 specific substrates. 33,34,76,77 However, based on our findings in this study we consider the SRL-peptide linker to be superior for our approach. This statement may be considered as based on circumstantial findings; however, we observed release of the SRL-linked fluorophore only in the presence of APMA activated MMP-9 or in the presence of the supernatant of proliferating HCASMC, while the release of the model compound linked to the AVR-peptide was observed in the presence of both gelatinases and the supernatant of both cell types.…”

An Overview of Highly Efficient Prodrug Strategies In Design, Development, Bioactive Pathway and Recent Therapeutic Applications

“…Carbonyl moiety: The compounds containing carbonyl functionalities such as ketone and aldehydes converted to prodrugs have not found wide clinical utility. These are converted into derivatives in which the sp 2 carbon of carbonyl enzymes to make their active forms [50] .…”