TY - JOUR
T1 - Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis
AU - Yin, Qian
AU - Tang, Li
AU - Cai, Kaimin
AU - Tong, Rong
AU - Sternberg, Rachel
AU - Yang, Xujuan
AU - Dobrucki, Lawrence W.
AU - Borst, Luke B.
AU - Kamstock, Debra
AU - Song, Ziyuan
AU - Helferich, William G.
AU - Cheng, Jianjun
AU - Fan, Timothy M.
N1 - Funding Information:
This work was supported by Morris Animal Foundation for the conductance of the phase I dose-escalation study in pet dogs with osteosarcoma, Grant D09CA-083 (to T.M.F.); NIH Director's New Innovator Award Program Grant 1DP2OD007246-01, which supported in vitro and in vivo studies, and National Science Foundation Division of Materials Research Grant 1309525, which supported the synthesis of materials (both to J.C.); and NIH National Cancer Institute Alliance for Nanotechnology in Cancer "Midwest Cancer Nanotechnology Training Centre" Grant R25 CA154015A (to Q.Y., L.T., and K.C.).
PY - 2016/8/9
Y1 - 2016/8/9
N2 - 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 bonetargeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
AB - 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 bonetargeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.
KW - Canine comparative oncology
KW - Focal skeletal malignant osteolysis
KW - Large mammalian tumor model|osteosarcoma targeted therapy
KW - Nanoconjugate drug delivery
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U2 - 10.1073/pnas.1603316113
DO - 10.1073/pnas.1603316113
M3 - Article
C2 - 27457945
AN - SCOPUS:84982893809
SN - 0027-8424
VL - 113
SP - E4601-E4609
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -