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Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency.

ABSTRACT: Systemic drug delivery to a solid tumor involves a sequence of steps that determine efficacy and survival. Extravasation from circulation at the tumor site is a critical step in this sequence since it regulates how much of the drug accumulates in the tumor. Despite its importance in determining outcomes, extravasation from circulation remains a "black box." The objective of this study is to develop predictive tools for optimization of drug delivery systems. By comparing pharmacokinetics of liposomal doxorubicin in tumor-free and tumor bearing mice we quantitatively assess the rate constants for distribution, elimination, and tumor accumulation. We then relate these rate constants to the tumor-type and drug delivery system. We compare tumor accumulation in three tumor types and show a 10-fold difference between a colorectal adenocarcinoma and a pancreatic adenocarcinoma. Finally, we show how quantitative predictions of changes in tumor accumulation can be used to optimize drug delivery systems.

SUBMITTER: Dawidczyk CM

PROVIDER: S-EPMC5538251 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency.

Dawidczyk Charlene M CM Russell Luisa M LM Hultz Margot M Searson Peter C PC

Nanomedicine : nanotechnology, biology, and medicine 20170228 5

Systemic drug delivery to a solid tumor involves a sequence of steps that determine efficacy and survival. Extravasation from circulation at the tumor site is a critical step in this sequence since it regulates how much of the drug accumulates in the tumor. Despite its importance in determining outcomes, extravasation from circulation remains a "black box." The objective of this study is to develop predictive tools for optimization of drug delivery systems. By comparing pharmacokinetics of lipos ...[more]

PMID: 28254372

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Project description:Cardiotoxicity is the major dose-limiting factor in the chemotherapeutic use of doxorubicin (Dox). A delivery vehicle that can be triggered to release its payload in the tumoral microvasculature but not in healthy tissue would help improve the therapeutic window of the drug. Delivery strategies combining liposomal encapsulated Dox (LDox), microbubbles (MBs), and ultrasound (US) have been shown to improve therapeutic efficacy of LDox, but much remains to be known about the mechanisms and the US conditions that maximize cytotoxicity using this approach. In this study, we compared different US pulses in terms of drug release and acute toxicity. Drug uptake and proliferation rates using low-intensity US were measured in squamous cell carcinoma cells exposed to LDox conjugated to or coinjected with polymer MBs. The aims of this study were: (1) to compare the effects of low- and high-pressure US on Dox release kinetics; (2) to evaluate whether conjugating the liposome to the MB surface (DoxLPX) is an important factor for drug release and cytotoxicity; and (3) to determine which US parameters most inhibit cell proliferation and whether this inhibition is mediated by drug release or the MB/US interaction with cells. Low-pressure US (170 kPa) at high duty cycle (stable cavitation) released up to ∼ 70% of the encapsulated Dox from the DoxLPX, thus improving Dox bioavailability and cellular uptake and leading to a significant reduction in cell proliferation at 48 h. Flow cytometry showed that US generating stable oscillations of DoxLPX significantly increased cellular Dox uptake at 4 h after US exposure compared to LDox. Drug uptake was correlated with cytotoxicity at 48 h. Our results demonstrate that Dox-containing liposomes conjugated to polymer MBs can be triggered to release ∼ 70% of their payload using noninertial US. Following release, Dox became bioavailable to the cells and induced significantly higher cytotoxicity compared to nonreleased encapsulated drug. Our findings show promise for targeted drug delivery using this theranostic delivery platform at low US intensities.

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.

Dataset Information

Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency.

Publications

Tumor accumulation of liposomal doxorubicin in three murine models: Optimizing delivery efficiency.

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