Conjugates for Angiogenesis Targeted Radiotherapy Compound RadiolabelTarget

DOTA-E- c(RGDfK)2 Y-90 aVß3 integrin

DTPA-Tyr3-octreotate-c(RGDyD) In-111 aVß3 integrin

HPMA copolymer-RGD4C Y-90 aVß3 integrin

Tumor Model Reference

OVCAR-3 human ovarian carcinoma 107, 205

CA20948 & AR42J rat 206,207

pancreatic tumor

DU145 human prostate carcinoma 108

of free radical scavengers such as gentisic acid (GA) and ascorbic acid (AA), together with storage at low temperature ( — 78°C), stabilized the labeled compound for at least two half-lives of 90Y, even at a high specific activity.177

To develop an HPMA copolymer, RGD-based targeted angiogenesis imaging and therapy agent, the biodistribution and tumor accumulation of HPMA copolymer-RGD4C conjugate as compared to a control conjugate containing the tripeptide Arg-Gly-Glu (HPMA copolymer-RGE4C conjugate) has been studied.178 Figure 9.3 shows the scintigraphic image of SCID mice bearing prostate tumor xenografts 24 h post-injection of the conjugates. The HPMA copolymer-RGD4C conjugate shows greater tumor accumulation than the control. The tumor uptake of HPMA copolymer-RGD4C conjugate (4.6+ 1.8% injected dose/g) at 24 h post-injection was significantly higher than the control (1.2 + 0.1%). A time-dependent biodistribution study showed sustained tumor accumulation of HPMA copolymer-RGD4C conjugate, efficient background clearance, and increasing T/B ratios over time. High T/B increases both tumor detection and therapeutic ratio.178 Another advantage of using a polymeric conjugate of RGD was highlighted by comparing the biodistributions of HPMA copolymer-RGD4C conjugates and free RGD4C.23 Organ distribution data in two murine xenograft human prostate models indicated higher tumor accumulation and lower extravasation in normal tissues for HPMA copolymer conjugates compared to free RGD4C peptides (Figure 9.4). Also, T/B was significantly higher for the macromolecular conjugate. These conjugates may be particularly advantageous for cancer radiotherapy because the combination of polyvalent interaction and EPR effect would help to retain the conjugate in the tumor, enhancing the radiation dose.108,158

The use of a water-soluble polymer (HPMA)-based conjugate of RGD peptide and the acyclic chelator cyclohexyl-diethylenetriamine pentaacetic acid (CHX-A"-DTPA) for angiogenesis directed (90Y) radiotherapy has been studied.108 After intravenous injection in prostate carcinoma

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