Zhiwen Yao

Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel.

ABI-007, an albumin-bound, 130-nm particle form of paclitaxel, was developed to avoid Cremophor/ethanol-associated toxicities in Cremophor-based paclitaxel (Taxol) and to exploit albumin receptor-mediated endothelial transport. We studied the antitumor activity, intratumoral paclitaxel accumulation, and endothelial transport for ABI-007 and Cremophor-based paclitaxel. Antitumor activity and mortality were assessed in nude mice bearing human tumor xenografts [lung (H522), breast (MX-1), ovarian (SK-OV-3), prostate (PC-3), and colon (HT29)] treated with ABI-007 or Cremophor-based paclitaxel. Intratumoral paclitaxel concentrations (MX-1-tumored mice) were compared for radiolabeled ABI-007 and Cremophor-based paclitaxel. In vitro endothelial transcytosis and Cremophor inhibition of paclitaxel binding to cells and albumin was compared for ABI-007 and Cremophor-based paclitaxel. Both ABI-007 and Cremophor-based paclitaxel caused tumor regression and prolonged survival; the order of sensitivity was lung > breast congruent with ovary > prostate > colon. The LD(50) and maximum tolerated dose for ABI-007 and Cremophor-based paclitaxel were 47 and 30 mg/kg/d and 30 and 13.4 mg/kg/d, respectively. At equitoxic dose, the ABI-007-treated groups showed more complete regressions, longer time to recurrence, longer doubling time, and prolonged survival. At equal dose, tumor paclitaxel area under the curve was 33% higher for ABI-007 versus Cremophor-based paclitaxel, indicating more effective intratumoral accumulation of ABI-007. Endothelial binding and transcytosis of paclitaxel were markedly higher for ABI-007 versus Cremophor-based paclitaxel, and this difference was abrogated by a known inhibitor of endothelial gp60 receptor/caveolar transport. In addition, Cremophor was found to inhibit binding of paclitaxel to endothelial cells and albumin. Enhanced endothelial cell binding and transcytosis for ABI-007 and inhibition by Cremophor in Cremophor-based paclitaxel may account in part for the greater efficacy and intratumor delivery of ABI-007.

Glucose-insulin kinetics of the extravascular bioartificial pancreas : a study using microencapsulated rat islets

The success of the extravascular bioartificial pancreas (BAP) is contingent on the rapid transfer of the transfer of the glycemic signal across both an extravascular compartment and a semipermeable membrane and of insulin from the BAP to the recipient. To examine the possibility of microencapsulated islets such as the BAP to achieve satisfactory in vivo glucose-insulin kinetics, islets were isolated from Lewis rats, encapsulated in poly-L-lysine-alginate membrances, and isogenically transplanted into the peritoneal cavity of 14 streptozotocin induced diabetic rats. Fasting blood glucose (BG) was measured and intravenous glucose tolerance was tested at 8–10 weeks and compared with three control groups: 1) normal lewis rats (n=6); 2) untreated diabetic rats (n = 5); and 3) diabetic rats that received intraperitoneal implants of empty capsules (n = 4). Ten animals that received microencapsulated islets (5,271 ±431) promptly became normoglycemic, with a mean BG of 128 ± 17 ng/dl 3 days after transplantation and maintained this level > 100 days. Intravenous glucose tolerance K-value for the group was 3.84 ± 0.32 compared with 3.96 ± 0.39 (p = 0.83) for the normal control group, and 0.60 ± 0.12 (p < 0.01) and 0.40 ± 0.15 (p < 0.01) for the diabetic control groups with and without empty capsules. The authors conclude from these results that, given sufficient β-cell mass, a BAP without any vascular access can respond appropriately to an increase in blood glucose concentration, without overshoot hypoglycemia and within a lag lapse compatible with normal physiologic insulin delivery. This may have important implications for the final effects of microencapsulated islet transplantation on the secondary complications of diabetes.