Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy

Mitra, Amitava; Nan, Anjan; Papadimitriou, John C.; Ghandehari, Hamidreza; Line, Bruce R.

doi:10.1016/j.nucmedbio.2005.09.005

« Previous Next »Nuclear Medicine and Biology
Volume 33, Issue 1 , Pages 43-52, January 2006

Polymer-peptide conjugates for angiogenesis targeted tumor radiotherapy

Amitava Mitra
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA
- Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201, USA
Anjan Nan
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA
- Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201, USA
John C. Papadimitriou
- Department of Pathology, University of Maryland, Baltimore, MD 21201, USA
Hamidreza Ghandehari
- Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21201, USA
- Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201, USA
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
- Corresponding authors. Bruce R. Line is to be contacted at Division of Nuclear Medicine, Department of Radiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Tel.: +1 410 328 6888; fax: +1 410 328 1600. Hamidreza Ghandehari, Department of Pharmaceutical Sciences, Center for Nanomedicine and Cellular Delivery, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. Tel.: +1 410 706 8650; fax: +1 410 706 5017.
Bruce R. Line
- Center for Nanomedicine and Cellular Delivery, University of Maryland, Baltimore, MD 21201, USA
- Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA
- Division of Nuclear Medicine, Department of Radiology, University of Maryland, Baltimore, MD 21201, USA
- Corresponding authors. Bruce R. Line is to be contacted at Division of Nuclear Medicine, Department of Radiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Tel.: +1 410 328 6888; fax: +1 410 328 1600. Hamidreza Ghandehari, Department of Pharmaceutical Sciences, Center for Nanomedicine and Cellular Delivery, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. Tel.: +1 410 706 8650; fax: +1 410 706 5017.

Received 29 July 2005; received in revised form 7 September 2005; accepted 12 September 2005.

Abstract

Introduction

New methods of delivering radiotherapy to sites of occult or disseminated cancer are needed to control the disease and address the failure of conventional therapy. Because tumor cells rely on angiogenesis for survival, we assessed the effectiveness of β-emitter radiotherapy delivered by polymer-peptide conjugates that target tumor neovasculature. This molecularly targeted radiation is intended to damage both the endothelial bed and surrounding neoplastic cells.

Methods

N-(2-Hydroxypropyl) methacrylamide (HPMA), a biocompatible and water-soluble copolymer, was derivatized to incorporate side chains for ^99mTc and ⁹⁰Y chelation and was further conjugated to a α_Vβ₃ integrin-targeting peptide (RGD4C). The HPMA copolymer-RGD4C conjugate was characterized by its side-chain contents, in vitro endothelial cell adhesion assay and its biodistribution and antitumor effectiveness in a SCID mouse xenograft model of human prostate carcinoma.

Results

The conjugate contained about 16 RGD4C moieties per polymer backbone. Tumor accumulation significantly increased (P<.01) over time from 1.05±0.03 % injected dose (%ID)/g tissue at 1 h to 4.32±0.32% at 72 h. The activity in major normal tissues significantly decreased (P<.05) during that period. At 21 days, the control tumors increased 442% in volume from baseline. In contrast, a 7% and a 63% decrease of tumor volume were observed for the 100- and 250-μCi ⁹⁰Y treatment groups, respectively. Histopathological examination revealed increased apoptosis in the treated tumors with no acute signs of radiation-induced toxicity to other organs.