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Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice.

ABSTRACT: We report the in vivo efficacy, in tumor-bearing mice, of cancer prodrugs consisting of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) conjugated to doxorubicin (DOX). Our synthesis of polyMPC-DOX conjugates established prodrugs with tunable drug loading, pH sensitive release kinetics, and a maximum tolerated dose in the range of 30-50 mg/kg (DOX equivalent) in healthy mice. Here we show prolonged circulation of polyMPC-DOX, with a measured in vivo half-life (t1/2) 8 times greater than that of the free drug. We observed reduced drug uptake in healthy tissue, and 2-3 times enhanced drug accumulation in tumors for polyMPC-DOX prodrugs compared to free DOX, using BALB/c mice bearing 4T1 tumors. Prolonged survival and reduced tumor growth were observed in mice receiving the polyMPC-DOX prodrug treatment. Moreover, we evaluated immunogenicity of polyMPC-DOX prodrugs by examining complete blood count (CBC) and characteristic cytokine responses, demonstrating no apparent innate or adaptive immune system response.

SUBMITTER: McRae Page S

PROVIDER: S-EPMC4018119 | biostudies-other | 2014 May

REPOSITORIES: biostudies-other

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Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice.

McRae Page Samantha S Henchey Elizabeth E Chen Xiangji X Schneider Sallie S Emrick Todd T

Molecular pharmaceutics 20140421 5

We report the in vivo efficacy, in tumor-bearing mice, of cancer prodrugs consisting of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) conjugated to doxorubicin (DOX). Our synthesis of polyMPC-DOX conjugates established prodrugs with tunable drug loading, pH sensitive release kinetics, and a maximum tolerated dose in the range of 30-50 mg/kg (DOX equivalent) in healthy mice. Here we show prolonged circulation of polyMPC-DOX, with a measured in vivo half-life (t1/2) 8 times greater than t ...[more]

PMID: 24750072

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Project description:Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB. Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively. Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain tumors and could become a promising new therapeutic option for the treatment of brain malignancies.

Project description:PURPOSE:Cyclophosphamide is widely used to treat children with medulloblastoma; however, little is known about its brain penetration. We performed cerebral microdialysis to characterize the brain penetration of cyclophosphamide (130 mg/kg, IP) and its metabolites [4-hydroxy-cyclophosphamide (4OH-CTX) and carboxyethylphosphoramide mustard (CEPM)] in non-tumor bearing mice and mice bearing orthotopic Group 3 medulloblastoma. METHODS:A plasma pharmacokinetic study was performed in non-tumor-bearing CD1- nude mice, and four cerebral microdialysis studies were performed in non-tumor-bearing (M1 and M3) and tumor- bearing mice (M2 and M4). Plasma samples were collected up to 6-hours post-dose, and extracellular fluid (ECF) samples were collected over 60-minute intervals for 24-hours post-dose. To stabilize and quantify 4OH-CTX, a derivatizing solution was added in blood after collection, and either directly in the microdialysis perfusate (M1 and M2) or in ECF collection tubes (M3 and M4). Plasma/ECF cyclophosphamide and CEPM, and 4OH-CTX concentrations were separately measured using different LC-MS/MS methods. RESULTS:All plasma/ECF concentrations were described using a population-based pharmacokinetic model. Plasma exposures of cyclophosphamide, 4OH-CTX, and CEPM were similar across studies (mean AUC=112.6, 45.6, and 80.8 µmol?hr/L). Hemorrhage was observed in brain tissue when the derivatizing solution was in perfusate compared with none when in collection tubes, which suggested potential sample contamination in studies M1 and M2. Model-derived unbound ECF to plasma partition coefficients (Kp,uu) were calculated to reflect CNS penetration of the compounds. Lower cyclophosphamide Kp,uu was obtained in tumor-bearing mice versus non-tumor bearing mice (mean 0.15 versus 0.22, p=0.019). No differences in Kp,uu were observed between these groups for 4OH- CTX and CEPM (overall mean 0.10 and 0.07). CONCLUSIONS:Future studies will explore potential mechanisms at the brain-tumor barrier to explain lower cyclophosphamide brain penetration in tumor-bearing mice. These results will be used to further investigate exposure-response relationships in medulloblastoma xenograft models.

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Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice.

Publications

Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice.

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