Uptake of ANG1005, A Novel Paclitaxel Derivative, Through the Blood-Brain Barrier into Brain and Experimental Brain Metastases of Breast Cancer

Abstract

Purpose We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. Methods The transfer coefficient (Kin) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB-231BR metastases of breast cancer. Results The BBB Kin for 125I-ANG1005 uptake (7.3 ± 0.2 × 10−3 mL/s/g) exceeded that for 3H-paclitaxel (8.5 ± 0.5 × 10−5) by 86 fold. Over 70% of 125I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain 125I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of 125I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of 14C-paclitaxel by 4–54 fold. Conclusions The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel.

Paclitaxel–Hyaluronic NanoConjugates Prolong Overall Survival in a Preclinical Brain Metastases of Breast Cancer Model

“…Several strategies have been used to circumvent P-gp at BBB, including chemical modification, (47) encapsulating in nanoparticles (48), and conjugating to peptide vectors (49)(50)(51)(52). Our data suggest that HA-paclitaxel bypasses P-gp, and the cellular uptake of the conjugate is approximately 10-fold greater than that of free paclitaxel.…”

Specific Amyloid β Clearance by a Catalytic Antibody Construct

“…Routes toward improving the IgV longevity and BBB penetration properties are available (e.g. attachment of an appropriate polypeptide tag) (47)(48)(49).…”

ANG4043, a Novel Brain-Penetrant Peptide–mAb Conjugate, Is Efficacious against HER2-Positive Intracranial Tumors in Mice

“…Median survival in the ANG4043 group was 60 days (95% CI, 50-63). In a follow-up study to determine the effect of increasing dose, intravenous treatment with 15 mg/kg ANG4043 increased median survival by 78% (P ¼ 0.0003), with survival of 45 days (95% CI, [40][41][42][43][44][45][46][47][48][49] in the vehicle group and 80 days (95% CI, 62-89) in the ANG4043 group (Fig. 6B).…”

“…Mice (n ¼ 10) in the survival studies were monitored daily for body weight loss and were euthanized if a reduction of 20% or greater from the maximum weight was observed. For the native mAb, median survival was somewhat higher than for vehicle (6%, P ¼ 0.028), with vehicle and anti-HER2 median survival of 47 days [95% confidence interval (CI), [40][41][42][43][44][45][46][47][48][49][50] and 50 days (95% CI, 45-56), respectively (Fig. 6A).…”