The synthesis and biodistribution of three triazine dendrimers differing in PEGylation are described. Dendrimers 1, 2, and 3 are derived from a common intermediate, dendrimer 4, and vary in molecular mass from 11 to 73 kDa as a result of PEGylation with multiple (theoretically, 16) PEG groups of 0.6, 2, and 5 kDa, respectively. As expected, elimination half-lives increased with an increase in molecular mass. In light of other results, however, molecular mass proves not to be the primary determinant of elimination half-lives. Instead, these times can be more readily predicted from the number of PEG groups on the dendrimer: the size of the PEG chain contributes to a lesser extent. Tumor uptake is observed for all the three dendrimers in mice bearing prostate cancer xenografts.

The use of lanthanide-based contrast agents for magnetic resonance imaging (MRI) has become an integral component of this important diagnostic modality. These inert chelates typically possess high thermodynamic stability constants that serve as a predictor for in vivo stability and low toxicity. Recently a new class of contrast agents was reported having a significantly lower degree thermodynamic stability while exhibiting biodistribution profiles indicative of high stability under biological conditions. These observations are suggestive that the nature of contrast agent stability is also dependent upon the kinetics of complex dissociation; a feature of potential importance when contemplating the design of new chelates for in vivo use. In this paper we present a study of the kinetics of acid catalyzed dissociation, thermodynamic stability, serum stability and biodistribution of a series of DOTA-tetraamide complexes that have been substituted with peripheral hydroxyl groups. The data indicate that these non-traditional contrast agents exhibit in vivo stability comparable to agents with much higher log K ML values demonstrating the important contribution of kinetic inertness.

A hybrid compound (DO3A-BP) featuring a radiometal bifunctional chelator (1,4,7,N',N", DOTA) and an osteoclast-targeting moiety (bisphosphonate) was designed and synthesized. The 111 In-labeled complex of DO3A-BP showed significantly elevated uptake in osteoclasts compared to the undifferentiated adherent bone marrow derived cells. Biodistribution studies revealed a favorable tissue distribution profile in normal mice with high bone uptake and long retention, and low or negligible accumulation in non-target organs. KeywordsBone metastasis; imaging agent; osteoclast; Indium-111; bifunctional chelator; bisphosphonate A variety of cancers preferentially metastasize to the skeleton at their advanced stages. Wholebody scan using 99m Tc-MDP (MDP: methylene diphosphonate) is currently the standard clinic practice for the detection of bone metastases. 1, 2 However, due to its low specificity a final diagnosis is often aided by other imaging modalities, such as X-ray radiography, magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography, and/ or bone marrow biopsy. 3, 4 Of the clinical methods to treat bone metastases, therapies utilizing bisphosphonates (BPs) and radiopharmaceuticals play critical roles. To date, several BPs have been approved by the FDA 5 and they are commonly used to treat skeletal complications caused by metastases and other bone diseases, including tumor-associated osteolysis, 6, 7 hypercalcemia, 8 Paget's disease, 9, 10 and osteoporosis. 11 As shown in Figure 1, bisphosphonates are a group of compounds with a chemical structure similar to that of the natural inorganic pyrophosphate (PPi), an endogenous regulator of bone mineralization, but differing in the central atom where BPs have a methylene carbon rather than an oxygen atom in PPi. This structural feature renders BPs resistant to hydrolysis under acidic conditions or by pyrophosphatases. Varieties of BPs could be obtained by tuning the R 2 side chain while leaving the R 1 group intact as either -OH or -H. 12 It has recently become clear that BPs first bind avidly to the bone mineral surface and are subsequently internalized selectively by osteoclasts, where they inhibit the osteoclastic activity and induce apoptosis. In addition, BPs have been *Corresponding author. Tel.: +1 214 645 5978; fax: +1 214 645 5885; email: Xiankai.Sun@UTSouthwestern.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. found to inhibit tumor cell adhesion to mineralized bone as well as tumor cell invasion and proliferation. 13, 14 NIH Public AccessAuthor Manuscript Bioorg Med Chem Lett. ...