Clinical trials of
radiotherapy to control drug delivery were initiated in 1999 at Vanderbilt University. The initial studies exploited the findings that platelets are activated in
tumor blood vessels after high-dose irradiation as used in radiosurgery and high-dose-rate
brachytherapy. Platelets labeled with 111In showed binding in
tumor blood vessels. However, the platelet labeling process caused platelets to also accumulate in the spleen. That clinical trial was closed, and subsequent clinical trials targeted
protein activation in irradiated
tumor blood vessels. Preclinical studies showed that
peptide libraries that bind within irradiated
tumor blood vessels contained the
peptide sequence
Arg-Gln-Asp (RGD). RGD binds to
integrin receptors (e.g., receptors for
fibrinogen,
fibronectin, and
vitronectin). We found that the
fibrinogen receptor (GPIIb/IIIa, alpha2bbeta3) is activated within irradiated
tumor blood vessels. RGD peptidemimetics currently in clinical trials include GPIIb/IIIa antagonists and the platelet-imaging agent biapcitide. Biapcitide is an RGD mimetic that is labeled with 99Tc to allow
gamma camera imaging of the biodistribution of the GPIIb/IIIa receptor in
neoplasms of patients treated with radiosurgery. This study has shown that the schedule of administration of the RGD mimetic is crucial. The
peptide mimetic must be administered immediately before irradiation, whereas the natural
ligands to the receptor compete for biapcitide binding if biapcitide is administered after irradiation. The authors currently are conducting a dose deescalation study to determine the threshold dosage required for RGD mimetic binding to radiation activated receptor. Radiation-guided clinical trials have been initiated by use of high-dose-rate
brachytherapy. In a separate trial, the pharmacokinetics of radiation-inducible gene therapy are being investigated. In this trial, the radiation-activated promoter Egr-1 regulates expression of the
tumor necrosis factor alpha gene, which is administered by use of the attenuated adenovirus vector. The Ad.Egr-TNF (ADGV) gene is administered by intratumoral injection of vector followed by irradiation in patients with
soft-tissue sarcomas. This review highlights recent findings in these phase I pharmacokinetic studies of radiation-controlled drug delivery systems.