Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

Chaudhuri, Tista Roy; Arnold, Robert D.; Yang, Jun; Turowski, Steven G.; Qu, Yang; Spernyak, Joseph A.; Mazurchuk, Richard; Mager, Donald E.; Straubinger, Robert M.

doi:10.1007/s11095-012-0823-4

Cited by 15 publications

(18 citation statements)

References 49 publications

(65 reference statements)

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“…A myriad of molecular approaches have been used to improve the tumor distribution of macromolecular therapeutics including: tumor penetrating peptides [6–8], hyperthermia [9,10], degradable nanoparticles [11], enzymes and small molecules that modify the tumor ECM [12–16], vascular priming [17], and vascular normalization [18,19]. The effectiveness of these approaches depends on the pharmacology of the drug and the biology of the tumor.…”

Section: Introductionmentioning

confidence: 99%

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

Kohli

Kivimäe

Tiffany

et al. 2014

Journal of Controlled Release

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Liposomes improve the pharmacokinetics and safety of rapidly cleared drugs, but have not yet improved the clinical efficacy compared to the non-encapsulated drug. This inability to improve efficacy may be partially due to the non-uniform distribution of liposomes in solid tumors. The tumor extra-cellular matrix is a barrier to distribution and includes the high molecular weight glycosaminoglycan, hyaluronan (HA). Strategies to remove HA or block its synthesis may improve drug delivery into solid tumors. Orally administered methylumbelliferone (MU) is an inhibitor of HA synthesis, but it is limited by low potency and limited solubility. In this study, we encapsulate a water-soluble phosphorylated prodrug of MU (MU-P) in a liposome (L-MU-P). We demonstrate that L-MU-P is a more potent inhibitor of HA synthesis than oral MU in the 4T1 murine mammary carcinoma model using both a quantitative ELISA and histochemistry. We show that HA depletion improves the tumor distribution of liposomes computed using Mander’s colocalization analysis of liposomes with the tumor vasculature. Hyaluronan depletion also increases the fraction of the tumor area positive for liposomes. This improved distribution extends the overall survival of mice treated with Doxil®.

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Section: Introductionmentioning

confidence: 99%

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

Kohli

Kivimäe

Tiffany

et al. 2014

Journal of Controlled Release

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“…Formulation of drugs encapsulated in liposomes can increase their delivery to brain tumors after intravenous injection due to extended circulating half-life of the drug that permits tumor deposition via an impaired blood tumor barrier over time [1, 2]. However, few studies have investigated brain tissue uptake of liposomes after a short exposure following the intraarterial (IA) injections.…”

Section: Introductionmentioning

confidence: 99%

Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection

et al. 2014

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Rapid first pass uptake of drugs is necessary to increase tissue deposition after intraarterial (IA) injection. Here we tested whether brain tissue deposition of a nanoparticulate liposomal carrier could be enhanced by coordinated manipulation of liposome surface charge and physiological parameters, such as IA injection during transient cerebral hypoperfusion (TCH). Different degrees of blood-brain barrier (BBB) disruption were induced by focused ultrasound in three sets of Sprague Dawley rats. Brain tissue retention was then compared for anionic, cationic, and charge-neutral liposomes after IA injection combined with TCH. The liposomes contained a non-exchangeable carbocyanine membrane optical label that could be quantified using diffuse reflectance spectroscopy (DRS) or visualized by multispectral imaging. Real-time concentration-time curves in brain were obtained after each liposomal injection. Having observed greater tissue retention of cationic liposomes compared to other liposomes in all three groups, we tested uptake of cationic liposomes in C6 tumor bearing rats. DRS and multispectral imaging of postmortem sections revealed increased liposomal uptake by the C6 brain tumor as compared to non-tumor contralateral hemisphere. We conclude that regional deposition of liposomes can be enhanced without BBB disruption using IA injection of cationic liposomal formulations in healthy and C6 tumor bearing rats.

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“…A dried film of 9:5:1 mol:mol:mol distearoylphosphatidylcholine:cholesterol:polyethyleneglycol-derivatized phosphatidylethanolamine was hydrated with 250mM ammonium sulfate to a lipid concentration of 20mM, extruded through 80nm polycarbonate filters (25,26,30), and dialyzed against isotonic sucrose. The liposomes were remote-loaded (30,31) with 10.5 mg/ml DXR (drug:lipid 0.25:1 mol:mol).…”

Section: Methodsmentioning

confidence: 99%

Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model

Chaudhuri

Straubinger

Pitoniak

et al. 2016

Molecular Cancer Therapeutics

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Most pancreatic adenocarcinoma (PaCA) patients present with unresectable disease and benefit little from chemotherapy. Poor tumor perfusion and vascular permeability limit drug deposition. Previous work showed that smoothened inhibitors of hedgehog signaling (sHHI) promote neovascularization in spontaneous mouse models of PaCA and enhance tumor permeability to low-molecular weight compounds. Here we tested the hypothesis that sHHI can enhance tumor deposition and efficacy of drug-containing nanoparticles consisting of 80–100nm sterically-stabilized liposomes (SSL) containing doxorubicin (SSL-DXR). SCID mice bearing low-passage patient-derived PaCA xenografts (PDX) were pretreated po for 10 days with 40 mg/kg/day NVP-LDE225 (erismodegib), followed by i.v. SSL-DXR. Microvessel density, permeability, perfusion, and morphology were compared with untreated controls, as was SSL deposition and therapeutic efficacy. The sHHI alone affected tumor growth minimally, but markedly increased extravasation of nanoparticles into adenocarcinoma cell-enriched regions of the tumor. Immunostaining showed that sHHI treatment decreased pericyte coverage (α-SMA+) of CD31+ vascular endothelium structures, and increased the abundance of endothelium-poor (CD31−) basement membrane structures (collagen IV+), suggesting increased immature microvessels. SSL-DXR (15 mg/kg) administered after sHHI pretreatment arrested tumor volume progression and decreased tumor perfusion/permeability, suggesting an initial vascular pruning response. Compared to controls, one cycle of 10d sHHI pretreatment followed by 6 mg/kg SSL-DXR doubled median tumor progression time. Three cycles of treatment with sHHI and SSL-DXR, with a 10d between-cycle drug holiday, nearly tripled median tumor progression time. Based upon these data, short-term sHHI treatment sequenced with nanoparticulate drug carriers constitutes a potential strategy to enhance efficacy of pancreatic cancer therapy.

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Mechanisms of Tumor Vascular Priming by a Nanoparticulate Doxorubicin Formulation

Cited by 15 publications

References 49 publications

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

Improving the distribution of Doxil® in the tumor matrix by depletion of tumor hyaluronan

Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection

Tumor-Priming Smoothened Inhibitor Enhances Deposition and Efficacy of Cytotoxic Nanoparticles in a Pancreatic Cancer Model

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