Abstract:
:Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody-liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Geretti E,Leonard SC,Dumont N,Lee H,Zheng J,De Souza R,Gaddy DF,Espelin CW,Jaffray DA,Moyo V,Nielsen UB,Wickham TJ,Hendriks BSdoi
10.1158/1535-7163.MCT-15-0314subject
Has Abstractpub_date
2015-09-01 00:00:00pages
2060-71issue
9eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-15-0314journal_volume
14pub_type
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pub_type: 杂志文章
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更新日期:2009-04-01 00:00:00
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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更新日期:2004-09-01 00:00:00
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pub_type: 杂志文章
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更新日期:2014-08-01 00:00:00