title: Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer.
abstract: Advanced-stage prostate cancer usually metastasizes to bone and is untreatable due to poor biodistribution of intravenously administered anticancer drugs to bone. In this study, we modulated the surface charge/composition of biodegradable nanoparticles (NPs) to sustain their blood circulation time and made them small enough to extravasate through the openings of the bone's sinusoidal capillaries and thus localize into marrow. NPs with a neutral surface charge, achieved by modulating the NP surface-associated emulsifier composition, were more effective at localizing to bone marrow than NPs with a cationic or anionic surface charge. These small neutral NPs (~150nm vs. the more usual ~320nm) were also ~7-fold more effective in localizing in bone marrow than large NPs. We hypothesized that NPs that effectively localize to marrow could improve NP-mediated anticancer drug delivery to sites of bone metastasis, thereby inhibiting cancer progression and preventing bone loss. In a PC-3M-luc cell-induced osteolytic intraosseous model of prostate cancer, these small neutral NPs demonstrated greater accumulation in bone within metastatic sites than in normal contralateral bone as well as co-localization with the tumor mass in marrow. Significantly, a single-dose intravenous administration of these small neutral NPs loaded with paclitaxel (PTX-NPs), but not anionic PTX-NPs, slowed the progression of bone metastasis. In addition, neutral PTX-NPs prevented bone loss, whereas animals treated with the rapid-release drug formulation Cremophor EL (PTX-CrEL) or saline (control) showed >50% bone loss. Neutral PTX-NPs did not cause acute toxicity, whereas animals treated with PTX-CrEL experienced weight loss. These results indicate that NPs with appropriate physical and sustained drug-release characteristics could be explored to treat bone metastasis, a significant clinical issue in prostate and other cancers.
authors.affiliation: Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Isaac M
authors.initials: IM
authors.lastname: Adjei
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Blanka
authors.initials: B
authors.lastname: Sharma
authors.affiliation: Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Chiranjeevi
authors.initials: C
authors.lastname: Peetla
authors.affiliation: Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: labhasv@ccf.org.
authors.forename: Vinod
authors.initials: V
authors.lastname: Labhasetwar
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001853:Bone Marrow / Q000378:metabolism; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000556:secondary; D001862:Bone Resorption / Q000517:prevention & control*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008819:Mice, Nude; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D013499:Surface Properties; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D055114:X-Ray Microtomography
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel
keywords: Biodistribution; Bone marrow; Cancer therapy; Drug delivery; Nanomedicine