<i>In vitro</i> and <i>in vivo</i> evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

Daruwalla, Jurstine; Nikfarjam, Mehrdad; Greish, Khaled; Malcontenti‐Wilson, Caterina; Muralidharan, Vijayaragavan; Christophi, Christopher; Maeda, Hiroshi

doi:10.1111/j.1349-7006.2010.01679.x

Cited by 10 publications

(18 citation statements)

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“…200 lm in diameter). (29)(30)(31) In this study, we also found that Evans blue-bound albumin selectively accumulated in metastatic lung cancers by the EPR effect (Fig. 5c).…”

Section: Discussionsupporting

confidence: 73%

Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

et al. 2015

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Previously, we prepared a pirarubicin (THP)-encapsulated micellar drug using styrene–maleic acid copolymer (SMA) as the drug carrier, in which active THP was non-covalently encapsulated. We have now developed covalently conjugated SMA-THP (SMA-THP conjugate) for further investigation toward clinical development, because covalently linked polymer–drug conjugates are known to be more stable in circulation than drug-encapsulated micelles. The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation. Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect. As a result, remarkable antitumor effect was achieved against two types of tumors in mice without apparent adverse effects. Significantly, metastatic lung tumor also showed the EPR effect, and this conjugate reduced metastatic tumor in the lung almost completely at 30 mg/kg once i.v. (less than one-fifth of the maximum tolerable dose). Although SMA-THP conjugate per se has little cytotoxicity in vitro (1/100 of free drug THP), tumor-targeted accumulation by the EPR effect ensures sufficient drug concentrations in tumor to produce an antitumor effect, whereas toxicity to normal tissues is much less. These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.

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“…200 lm in diameter). (29)(30)(31) In this study, we also found that Evans blue-bound albumin selectively accumulated in metastatic lung cancers by the EPR effect (Fig. 5c).…”

Section: Discussionsupporting

confidence: 73%

Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

et al. 2015

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“…Control tissues were collected on day 21 post tumor induction. For the SMA-pirarubicin treatment mice with liver metastases were treated with a single IP dose of SMApirarubicin at 18 days post tumor induction [14]. Tissues were collected 3 days following treatment.…”

Section: Discussionmentioning

confidence: 99%

“…In the first treatment mice bearing liver metastases were treated with a single dose of the cytotoxic agent SMA-pirarubicin at 18 days post tumor induction. The drug dose of 250 mg/kg SMA-pirarubicin is equivalent to 100 mg free pirarubicin and was given intravenously via the tail vein in 0.2 mL saline solution [14]. Tissues from that study were collected at 3 days after treatment and stained for EMT markers.…”

Section: Other Treatment Modalitiesmentioning

confidence: 99%

“…Based on the findings with OXi4503 treatment in this study we hypothesized that similar morphological changes occur in other tumor treatments, we therefore examined archival tumor tissues from previous studies for evidence of EMT induction. In a previous study we reported significant tumor damage and acute hypoxia within residual tumors after treatment with the cytotoxic agent SMApirarubicin [14]. Tissues from that study, collected at 3 days after a single SMA-pirarubicin treatment, were stained for EMT markers.…”

Section: Chemotherapy and Other Treatment Modalities Of Liver Metastamentioning

confidence: 99%

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Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor

et al. 2013

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Epithelial to mesenchymal transition (EMT) is considered an important mechanism in tumor resistance to drug treatments; however, in vivo observation of this process has been limited. In this study we demonstrated an immediate and widespread EMT involving all surviving tumor cells following treatment of a mouse model of colorectal liver metastases with the vascular disruptive agent OXi4503. EMT was characterized by significant downregulation of E-cadherin, relocation and nuclear accumulation of β-catenin as well as significant upregulation of ZEB1 and vimentin. Concomitantly, significant temporal upregulation in hypoxia and the pro-angiogenic growth factors hypoxia-inducible factor 1-alpha, hepatocyte growth factor, vascular endothelial growth factor and transforming growth factor-beta were seen within the surviving tumor. The process of EMT was transient and by 5 days after treatment tumor cell reversion to epithelial morphology was evident. This reversal, termed mesenchymal to epithelial transition (MET) is a process implicated in the development of new metastases but has not been observed in vivo histologically. Similar EMT changes were observed in response to other antitumor treatments including chemotherapy, thermal ablation, and antiangiogenic treatments in our mouse colorectal metastasis model and in a murine orthotopic breast cancer model after OXi4503 treatment. These results suggest that EMT may be an early mechanism adopted by tumors in response to injury and hypoxic stress, such that inhibition of EMT in combination with other therapies could play a significant role in future cancer therapy.Vascular disruptive treatments effectively destroy over 90% of solid tumors with minimal effects on host tissues but a viable rim of cells persists in the tumor periphery that leads to recurrence. An immediate and widespread epithelial to mesenchymal transition (EMT) occurs within the viable rim after treatment that may be responsible for this resistance to treatment. Targeting EMT in combination with vascular disruptive agents or other therapies in the clinic may improve treatment outcomes.

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“…2,6 The amphiphilic nature of the styrene maleic acid (SMA) polymer has enabled the encapsulation of wide range of drugs. 9,11 The SMA system is especially well-suited for translational applications, due to the low costs of the polymer, simplicity of the synthetic process, and the ability to control the loading (up to 40% w/w) and release rate of active drugs in the micelle. 12 We anticipated that the amphiphilic nature of SMA micelle could enable it to pass through the mucosal barrier of the GI epithelium.…”

Section: Introductionmentioning

confidence: 99%

Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery – dual uptake through enterocytes and M-cells

Parayath¹,

Nehoff²,

Müller³

et al. 2015

IJN

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Drug delivery systems could potentially overcome low bioavailability and gastrointestinal toxicity, which are the major challenges for the development of oral anticancer drugs. Herein, we demonstrate the ability of styrene maleic acid (SMA) nanomicelles encapsulating epirubicin to traverse in vitro and ex vivo models of the intestinal epithelium without affecting the tissue integrity. Further, SMA micelles encapsulating a fluorescent dye dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI) showed twofold higher accumulation in the liver and spleen, 15-fold higher accumulation in the tumor, and sixfold higher accumulation in the lung as compared with the free DiI, following oral administration in a mice xenograft breast cancer model. Additionally, SMA micelles showed colocalization with microfold (M)-cells and accumulation in Peyer’s patches, which together confirms the M-cell mediated uptake and transport of SMA micelles. Our results indicate that SMA micelles, showing dual uptake by enterocytes and M-cells, are a potential tool for safe oral anticancer drug delivery.

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In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

Cited by 10 publications

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Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor

Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery – dual uptake through enterocytes and M-cells

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In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

Cited by 10 publications

References 0 publications

Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

Synthesis and therapeutic effect of styrene–maleic acid copolymer‐conjugated pirarubicin

Treatment with the vascular disruptive agent OXi4503 induces an immediate and widespread epithelial to mesenchymal transition in the surviving tumor

Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery &ndash; dual uptake through enterocytes and M-cells

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Styrene maleic acid micelles as a nanocarrier system for oral anticancer drug delivery – dual uptake through enterocytes and M-cells