This was thought to be secondary to the increased relative hydrophobicity of the former peptide construct. All other tissues analyzed demonstrated no significant difference in the magnitude of uptake of these peptides (data not shown) . The CTT2-peptide was thus selected for further studies given its more rapid hepatic clearance. Figure 4 Hepatic
accumulation of 125I-CTT2-peptides in normal mice. Liver accumulation of peptides per gram of tissue in normal mice (n = 5) relative to muscle (control). All values are expressed as the percentage of the control (% control) ± SD. In OV-90 xenograft models, substantially higher Inhibitors,research,lifescience,medical uptake of 125I-CTT2-peptide was measured in all organs/tissues (Figure 5), particularly in the xenograft, with tumor-to-blood ratios ~23 detected at 3 hrs postinjection (p.i.). This coupled with the poor prognosis of this disease in humans, showed the potential to improve treatment response using CTT2-peptide targeted
delivery, and the need to ensure controlled and sustained drug release led us to extend this model to investigate Inhibitors,research,lifescience,medical tumor uptake with micellar and liposomal Inhibitors,research,lifescience,medical formulations (Selleck Selisistat CTT2-micelles and CTT2-liposomes). The amount of CTT2-bound peptide available for liposomal targeting activity was found to be 500 based on the measured average size and surface area of the resulting peptide-bound liposomal product by dynamic light scattering and the aforementioned reaction conditions. Figure 5 Tissue distribution of a single dose of 125I-CTT2-peptide in immunosuppressed OV-90 xenograft mice. Blood and major organs/tissues were collected at 0.5hr and 3hrs p.i. 125I-CTT2-peptide (40μg/mouse, n = 5) and their … For doxorubicin-containing liposomes, doxorubicin leakage Inhibitors,research,lifescience,medical after peptide attachment was assessed by comparing free and liposomal doxorubicin on the basis Inhibitors,research,lifescience,medical of fluorometric analysis. Leakage was found to be minimal, with leakage before and after incorporation averaging 4.5% and 4.2%, respectively. Both OV-90 and mucinous ovarian carcinomas
(A2780) were thus selected as xenograft models for subsequent nanoformulation studies. In OV-90 tumor mice, clear targeting of CTT2-micelles was observed, reaching maximum values of 17.6% of the injected dose per gram (%ID/g) of tumor at 6hrs p.i. (Figure 6). Figure 6 Tissue distribution of 125I-CTT2-micelle in OV-90 tumor mice. %ID/g values after i.v. injection of CTT2-micelles (200μg/mouse, Non-specific serine/threonine protein kinase n = 5). All values are expressed as mean ± SD. Doxorubicin concentrations (μg doxorubicin per gram dry tissue), in the form of CTT2-SL (targeted) and SL (nontargeted Caelyx/Doxil) liposomes, were measured as a function of time p.i. in A2780 xenografts, as shown in Figure 7. Doxorubicin was delivered more efficiently and at a faster rate to tumors using CTT2-SL liposomal formulations compared to Caelyx, with significantly elevated tumoral levels of doxorubicin observed 3 days after drug injection.