Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse
Mi-Ran Choi
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2
Rizia Bardhan
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Katie J. Stanton-Maxey
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Sunil Badve
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Harikrishna Nakshatri
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Keith M. Stantz
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2
Ning Cao
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Naomi J. Halas
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Susan E. Clare
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S. Badve Department of Pathology and Laboratory Medicine, Indiana University School of Medicine
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Indianapolis, IN 46202, USA
1
) Department of Surgery, Indiana University School of Medicine
,
Indianapolis, IN 46202, USA
2
K. M. Stantz Department of Radiology and Imaging Sciences, Indiana University School of Medicine
,
Indianapolis, IN 46202, USA
As systemic cancer therapies improve and are able to control metastatic disease outside the central nervous system, the brain is increasingly the first site of relapse. The blood-brain barrier (BBB) represents a major challenge to the delivery of therapeutics to the brain. Macrophages originating from circulating monocytes are able to infiltrate brain metastases while the BBB is intact. Here, we show that this ability can be exploited to deliver both diagnostic and therapeutic nanoparticles specifically to experimental brain metastases of breast cancer.
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Brain metastases are a significant clinical challenge. They are
diagnosed in 100,000170,000 patients/year in the United
States (Posner 1992; Weil et al. 2005) and outnumber primary
brain tumors by a ratio of 10 to 1 (Cairncross and Posner 1983;
Walker et al. 1985; Posner 1992). They are estimated to occur in
2040 % of all cancer patients (Cairncross and Posner 1983;
Posner 1995). The incidence rate of brain metastasis is thought
to be increasing as a function of the aging population, better
treatment of non-central nervous system (CNS) disease and
improved imaging techniques. The most common primary
tumor sites are lung (4050 %), breast (1317 %), melanoma
(1117 %), renal (616 %), and GI tract (46 %)
(BarnholtzSloan et al. 2004; Klos and ONeill 2004). At least 10 % of
patients with primary small cell lung cancer (SCLC) have brain
metastasis at diagnosis (Hochstenbag et al. 2000; Grossi et al.
2001), however a more recent prospective study of 432 patients
in the Netherlands found the rate to be 18 % (Seute et al. 2004).
Patients with locally advanced non-small cell lung cancer are at
the highest risk for brain metastasis, with some studies reporting
greater than 50 % of patients developing brain metastasis over
the course of the disease (Stuschke et al. 1999).
Breast cancer metastatic to the brain is most prevalent in
the triple negative (Lin et al. 2008) and HER2+
subpopulations (Bendell et al. 2003; Clayton et al. 2004; Lin and
Winer 2007; Stemmler et al. 2006; Yau et al. 2006), where
the median survival time ranges from 2 to 16 months and the
mean 1-year survival is ~20 % (Mahmoud-Ahmed AS
2002). Since targeted therapies against HER2+ disease are
able to successfully control non-CNS disease, the brain is
increasingly being seen as the first site of relapse (Burstein
et al. 2005). Currently, the mainstays of treatment for
metastatic brain tumors are whole brain radiation therapy
(WBRT), surgery, stereotactic radiosurgery or a
combination of these modalities. However, significant neurotoxicity
has been reported with the use of WBRT, resulting in
endocrine dysfunction, significant memory loss and dementia
(Sneed et al. 1999; Patchell and Regine 2003; Lo et al. 2005).
Drug uptake into the brain is limited by numerous factors,
including physical barriers such as the bloodbrain barrier
(BBB) and the bloodcerebrospinal fluid (bloodCSF) barrier,
and a substrates affinity for specific transport systems located at
both of these interfaces (Graff and Pollack 2004; Pardridge
2005). Despite recent indications that chemical modulation of
the BBB may be feasible (Carman et al. 2011), under
physiological conditions, drugs and other substances can enter the
brain only by passive transcellular diffusion,
receptormediated transcytosis, or through the action of specific carrier
systems. While in general, the more lipid-soluble a molecule
is, the more readily it will penetrate the BBB and bloodCSF
barrier to reach targets in the CNS, many lipid-soluble
therapeutics have much lower brain permeability than would be
predicted on the basis of their solubility (Begley 2004;
Muldoon et al. 2007). In an experimental model of brain
metastases of breast cancer, cytotoxic concentrations of
paclitaxel were reached only in a subset (<10 %) of the leakiest
metastases (Lockman et al. 2010), and this therapy was unable
to reduce the metastatic burden in the brain over the period of
the study. All of these factors render the brain a sanctuary
site for metastases.
More than two decades ago, Fidler and colleagues provided
evidence that macrophages of blood monocyte origin can
infiltrate experimental brain metastases while the bloodbrain
barrier is intact (Schackert et al. 1988). Even earlier, Morantz and
colleagues had quantified the content of macrophages in
clinical specimens (Morantz et al. 1979). They examined 12
metastases to the brain from a variety of primary tumo (...truncated)