Abstract 2646: Biodistribution of multifunctional microparticles (APMS) for targeted delivery of chemotherapeutic drugs
Authors: Sherrill Lathrop , Hillegass Jedd , Steinbacher Jeremy , MacPherson Maximilian , Beuschel Stacie , Jerome Neil , Hakumäki J.M. , Kauppinen Risto A. , Landry Christopher , Mossman Brooke 
Published: February 2011

The toxicity associated with systemic administration of chemotherapeutics, especially in chemoresistant tumors such as malignant mesotheliomas (MMs), in combination with the low therapeutic efficacy of current treatments, has mandated localized delivery methods to target tumor cell populations. Here we describe the biodistribution of a micron-sized multifunctional amorphous silica particle (APMS) in normal rats and mice and in subcutaneous (SQ) and intraperitoneal (IP) SCID mouse xenograft models of MM.

To determine particle retention by tumor cells, APMS modified with an Alexa-647 fluorophore (APMS-A647) were injected (3.3×108 particles) either SQ or IP into tumor-bearing immunodeficient SCID mice or IP into C57/BL6 mice. APMS retention by tumor and organ cells at 24 hr or 1 week was analyzed via flow cytometry of single cell suspensions or microscopy on cells in pleural lavage fluid (PLF). In vivo visualization of APMS biodistribution was conducted by magnetic resonance imaging (MRI) of gadolinium-modified APMS (APMS-Gd) injected into Wistar rats (500 mg/kg). APMS biodistribution was determined by combining scanning electron microscopy (SEM) with electron dispersive spectroscopy (EDS) to identify silica within rat organs and in urine. In vivo targeting of antibody (anti-mesothelin) and Alexa fluorophore-modified APMS (APMS-MB-A488) to IP MM tumors in SCID mice was analyzed by ICP-MS and confocal microscopy.

Flow cytometry (FACS) analysis revealed that APMS-A647 administered to SQ MMs were retained by a higher percentage of viable tumor cells (2-3%) than lung, liver, spleen, kidney, or saline injected control tumor cells (0-0.5%). Analyses of APMS-A647 particles administered IP also showed higher percentages of viable MM cells associated with APMS and the retention of APMS in PLF fluid and cells as verified by SEM/EDS. MRI results revealed that some APMS-Gd injected IP into Wistar rats were excreted in urine. Further analysis of rat organ tissue via SEM/EDS revealed APMS-Gd in the liver, spleen, kidney and bladder tissue. ICP-MS analysis of showed increased APMS-MB-488 in IP MM tumor tissue in comparison to organs or non-targeted controls (APMS-BSA-488), and confocal microscopy shows increased florescence in MMs of targeted treatment groups as compared to non-targeted control groups.

APMS, when administered locally, are retained by tumor cells and are cleared via the urine. They do not appear to cause inflammation or necrosis in major organs. We are currently examining the ability to target APMS to IP tumors in vivo using anti-mesothelin antibodies, an approach that should further enhance specificity and uptake of APMS-encapsulated chemotherapeutic drugs by MM and other tumors (ovarian, pancreatic). Preliminary results of in vivo targeting of IP MM tumors suggests enhanced tumor uptake of APMS-MB-A488 in comparison to non-targeted APMS controls.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2646.