title: Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis.
abstract: Malignant osteolysis associated with inoperable primary bone tumors and multifocal skeletal metastases remains a challenging clinical problem in cancer patients. Nanomedicine that is able to target and deliver therapeutic agents to diseased bone sites could potentially provide an effective treatment option for different types of skeletal cancers. Here, we report the development of polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and coated with bone-seeking pamidronate (Pam) for the targeted treatment of malignant skeletal tumors. In vivo biodistribution of radiolabeled targeted Pam-NPs demonstrated enhanced bone tumor accumulation and prolonged retention compared with nontargeted NPs. In a murine model of focal malignant osteolysis, Pam-functionalized, Doxo-loaded NPs (Pam-Doxo-NPs) significantly attenuated localized osteosarcoma (OS) progression compared with nontargeted Doxo-NPs. Importantly, we report on the first evaluation to our knowlege of Pam-Doxo-NPs in dogs with OS, which possess tumors of anatomic size and physiology comparable to those in humans. The repeat dosing of Pam-Doxo-NPs in dogs with naturally occurring OS indicated the therapeutic was well tolerated without hematologic, nonhematologic, and cardiac toxicities. By nuclear scintigraphy, the biodistribution of Pam-Doxo-NPs demonstrated malignant bone-targeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Qian
authors.initials: Q
authors.lastname: Yin
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Li
authors.initials: L
authors.lastname: Tang
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Kaimin
authors.initials: K
authors.lastname: Cai
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Rong
authors.initials: R
authors.lastname: Tong
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Rachel
authors.initials: R
authors.lastname: Sternberg
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Xujuan
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Dobrucki
authors.affiliation: Department of Population Health and Pathobiology, North Carolina State University, Raleigh, NC 27606;
authors.forename: Luke B
authors.initials: LB
authors.lastname: Borst
authors.affiliation: Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523.
authors.forename: Debra
authors.initials: D
authors.lastname: Kamstock
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801; jianjunc@illinois.edu t-fan@illinois.edu.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801; jianjunc@illinois.edu t-fan@illinois.edu.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Fan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy*; D004164:Diphosphonates / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D058726:Nanoconjugates / Q000008:administration & dosage*; D010014:Osteolysis / Q000188:drug therapy*; D000077268:Pamidronate
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D058726:Nanoconjugates; D004317:Doxorubicin; D000077268:Pamidronate
keywords: canine comparative oncology; focal skeletal malignant osteolysis; large mammalian tumor model; nanoconjugate drug delivery; osteosarcoma targeted therapy