Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse

Cancer Nanotechnology, Jul 2012

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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Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse

Mi-Ran Choi 0 2 Rizia Bardhan 0 2 Katie J. Stanton-Maxey 0 2 Sunil Badve 0 2 Harikrishna Nakshatri 0 2 Keith M. Stantz 0 2 Ning Cao 0 2 Naomi J. Halas 0 2 Susan E. Clare 0 2 0 S. Badve Department of Pathology and Laboratory Medicine, Indiana University School of Medicine , 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. - 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)


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Mi-Ran Choi, Rizia Bardhan, Katie J. Stanton-Maxey, Sunil Badve, Harikrishna Nakshatri, Keith M. Stantz, Ning Cao, Naomi J. Halas, Susan E. Clare. Delivery of nanoparticles to brain metastases of breast cancer using a cellular Trojan horse, Cancer Nanotechnology, 2012, pp. 47-54, Volume 3, Issue 1-6, DOI: 10.1007/s12645-012-0029-9