Abstract 1947: Self-reporting dendritic nanoparticles (nanodendrons) for drug delivery targeted to the tumor microenvironment and with reduced neurotoxicity
Authors: Samuelson Lynn E. , Scherer Randy L. , Kathy Carter J. , Dozier E Ashley , Printz Sheree , VanSaun Michael N. , Fan Kang-Hsien , Shyr Y , Matrisian Paul E. , Bornhop Darryl J. , Matrisian Lynn M. , McIntyre J Oliver 
Published: August 2012

Abstract
Proteinases, including matrix metalloproteinases (MMPs), contribute to cancer progression and other pathologies. Selective MMP expression can be used to distinguish benign from malignant tumors and identify aggressive tumors associated with poor outcome. MMP9, a basement membrane-degrading type-IV collagenase/gelatinase, is associated with tumor invasion and metastasis. In this project, we describe a new class of dendritic nanoparticles, nanodendrons (NDs), with MMP molecular recognition and targeting capabilities. These NDs can be studied as individual dendrons tuned for specific functions such as enhanced imaging or targeted drug treatments. Additionally, the NDs can be coupled to facilitate multifunctional purposes such as in NDs that can self-report drug delivery to tumors. The prototypical system presented here describes NDs that are activated by MMP9: 1) ND-PB, a near infrared imaging beacon; 2) ND-PXL, a therapeutic that delivers paclitaxel (PXL) and 3) NDPB-NDPXL, a bi-functional agent. In vivo studies in two orthotopic models of breast cancer demonstrate efficacy of these NDs to image and treat breast cancer. The proteinase-activated prodrug, NDPXL, delivers PXL to breast cancer through release of the drug in the tumor microenvironment and increases therapeutic efficacy while reducing systemic toxicity (including peripheral neuropathy). The delivery of PXL using the proteolytically activated ND-PXL is effective in inhibiting tumor growth in two orthotopic models of breast cancer (PyVT-R221A and MDA-MB231). Daily treatment of MDA-MB231 tumors with 12.5 mg/kg PXL as either ND-PXL or Abraxane® (Abx), showed similar reduction in tumor growth as compared with vehicle-treated animals. Further investigation of the NDPXL in a fully immunocompetent mouse model (PyVT-R221A) with treatments given on alternate days at a dose of 12.5 mg/kg (ND-PXL or Abx) yielded similar results: an average reduction in tumor growth of 58% and 53% in ND-PXL and Abx cohorts, respectively. Peripheral nerve toxicity, a debilitating, long term side effect of Abx therapy, was assessed in both tumor and non-tumor mice through monitoring behavior indicative of peripheral nerve damage before, during and after administration of each drug. Peripheral neurotoxicity is markedly reduced in the ND-PXL-treated versus Abraxane®-treated mice as evident in a number of behavioral assessments. The development of this novel class of NDs expands upon the current capabilities of modern proteinase-based optical beacons and prodrugs and is a step forward in treatment of both primary and metastatic cancer. [Supported in part by Susan G. Komen for the Cure®]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1947. doi:1538-7445.AM2012-1947