The

The middle GSK1349572 aspartic acid block allows for a hydrogen-bonding segment which can be further stabilized with the use of metal ions, an aspect that is not utilized for IT-141. Figure 1 Diagram of the IT-141 formulation. ITP-101 consists

of poly(ethylene glycol)-b-poly(aspartic acid)-b-poly(D-leucine-co-tyrosine), where the hydrophobic amino acids provide Inhibitors,research,lifescience,medical a core region into which a hydrophobic drug can reside, and the amphiphilic PEG … IT-141 was formulated using ITP-101 with various concentrations of SN-38, ranging from 1 to 14% (w/w), achieving greater than 90% loading efficiency. Formulations of IT-141 reconstituted in water or saline resulted in a homogeneous solution free of precipitate for up to Inhibitors,research,lifescience,medical four days at room temperature, and the lyophilized powder is stable for months. Following formulation, the aqueous solubility of SN-38 in IT-141 was 30mg/mL, which is about a 6,000-fold increase in solubility of SN-38.

[25]. Dynamic light scattering (DLS) experiments demonstrated that the micelle size was approximately 130nm, with a standard deviation of ±6nm. Thus, the average size of IT-141 falls within the desired range to avoid renal clearance (above ~20nm) and escape uptake by the RES (below Inhibitors,research,lifescience,medical ~150nm). Zeta potential measurements from electrophoretic light scattering experiments demonstrated that the surface charge of the micelle is overall neutral, with a range of readings from −5 to 5mV. The sensitivity of various cancer Inhibitors,research,lifescience,medical cell

lines to free SN-38, IT-141, and irinotecan was compared in a cytotoxicity assay. As shown in Table 1, both free SN-38 and IT-141 were extremely potent, and the sensitivity of the cells to IT-141 was similar to free SN-38 across the cell lines. Irinotecan was several orders of magnitude less toxic Inhibitors,research,lifescience,medical than either free SN-38 or IT-141. Certain cell lines (PC-3, MDA-MB-231, and BT-474) were insensitive to both free SN-38 and IT-141. Table 1 IC50 values (μM) of IT-141 compared to free SN-38 and irinotecan in cancer cell lines. Data are presented as mean ± standard deviation. To determine the MTD of IT-141, HT-29 tumor-bearing nude mice were given both single and multidose (Q4D × 3) intravenous injections of IT-141. These studies demonstrated that the multidose MTD of IT-141 in tumor-bearing animals was 45mg/kg and single dose MTD was 60mg/kg. Using 30mg/kg of IT-141 as a safe dose, the pharmacokinetic (PK) profile and tumor accumulation unless of SN-38 delivered from IT-141 then compared to irinotecan in nude mice bearing HT-29 tumors (Table 2). Mice receiving a single injection of 30mg/kg IT-141 achieved a significant improvement in SN-38 plasma concentration and exposure compared to 30mg/kg of irinotecan (Figure 2(a), Table 2). The Cmax for both groups was achieved by the first measured time point of 5 minutes, with >200-fold higher SN-38 concentration in mice treated with IT-141 (209μg/mL) compared to irinotecan (1.0μg/mL).

This entry was posted in Uncategorized. Bookmark the permalink.

Leave a Reply

Your email address will not be published. Required fields are marked *

*

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>