ABSTRACT
MM-302 is an anti-HER2 antibody-targeted pegylated liposomal doxorubicin designed to deliver doxorubicin specifically to HER2-expressing solid tumors. The delivery and activity of MM-302 were evaluated in orthotopic, transgenic, and intravenous breast cancer models expressing varying levels of HER2 that metastasize to some of the most common sites of dissemination for breast cancer, namely, lung, liver, and brain. Metastatic burden was quantified by gross evaluation, immunohistochemistry (IHC), and bioluminescent imaging. Liposome delivery was quantified by IHC and ex vivo fluorescent imaging. Unlike its non-targeted counterpart, pegylated liposomal doxorubicin (PLD), MM-302 showed activity at controlling both primary and metastatic tumor burden in all models tested. The effect of HER2-targeting was greatest in the lung where lymphatic vessel density and MM-302 delivery were highest. Our data indicate that the therapeutic advantage of actively targeting a nanoliposome with an antibody is influenced by both target expression and the tumor microenvironment.
Subject(s)
Antibiotics, Antineoplastic/administration & dosage , Breast Neoplasms/drug therapy , Doxorubicin/analogs & derivatives , Immunoconjugates/chemistry , Liposomes/chemistry , Single-Chain Antibodies/chemistry , Animals , Antibiotics, Antineoplastic/therapeutic use , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Cell Line, Tumor , Disease Progression , Doxorubicin/administration & dosage , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Drug Delivery Systems , Female , Mice , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic use , Receptor, ErbB-2/metabolism , Tumor Microenvironment/drug effectsABSTRACT
PURPOSE: The purpose of this study was to cross-validate previously developed Actiwatch (AW; Ekblom et al. 2012) and AcitGraph (AG; Sirard et al. 2005; AG-P, Pate et al. 2006) cut-point equations to categorize free-living physical activity (PA) of preschoolers using direct observation (DO) as the criterion measure. A secondary aim was to compare output from the AW and the AG from previously developed equations. METHODS: Participants' (n = 33; age = 4.4 ± 0.8 yrs; females, n=12) PA was directly observed for three 10-min periods during the preschool-day while wearing the AW (nondominant wrist) and AG (waist). Device specific cut-points were used to reduce the AW-E (Ekblom et al. 2012) and AG (AG-S, Sirard et al. 2005; AG-P, Pate et al. 2006) data into intensity categories. Spearman correlations (rsp) and agreement statistics were used to assess associations between the DO intensity categories and device data. Mixed model regression was used to identify differences in times spent in activity intensity categories. RESULTS: There was a significant correlation between AW and AG output across all data (rsp = 0.41, p < .0001) and both were associated with the DO intensity categories (AW: rsp = 0.47, AG: rsp = 0.47; p < .001). At the individual level, all devices demonstrated relatively low sensitivity but higher specificity. At the group level, AW-E and AG-P provided similar estimates of time spent in moderate-to-vigorous PA (MVPA, AW-E: 4.7 ± 4.1, AG-P: 4.4 ± 3.3), compared with DO (5.1 ± 3.5). CONCLUSION: The AW-E and AG-P estimated times spent in MVPA were similar to DO, but the weak agreement statistics indicate that neither device cut-point equations provided accurate estimates at the individual level.
