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 bonetargeting capability and exerted measurable anticancer activities as confirmed with percent tumor necrosis histopathology assessment.

Original languageEnglish (US)
Pages (from-to)E4601-E4609
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number32
DOIs
StatePublished - Aug 9 2016

Fingerprint

pamidronate
Nanoconjugates
Osteolysis
Nanoparticles
Doxorubicin
Osteosarcoma
Neoplasms
Therapeutics
Bone and Bones
Dogs
Nanomedicine
Bone Diseases
Radionuclide Imaging

Keywords

  • Canine comparative oncology
  • Focal skeletal malignant osteolysis
  • Large mammalian tumor model|osteosarcoma targeted therapy
  • Nanoconjugate drug delivery

ASJC Scopus subject areas

  • General

Cite this

Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis. / Yin, Qian; Tang, Li; Cai, Kaimin; Tong, Rong; Sternberg, Rachel; Yang, Xujuan; Dobrucki, Lawrence W.; Borst, Luke B.; Kamstock, Debra; Song, Ziyuan; Helferich, William G.; Cheng, Jianjun; Fan, Timothy M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 32, 09.08.2016, p. E4601-E4609.

Research output: Contribution to journalArticle

Yin, Qian ; Tang, Li ; Cai, Kaimin ; Tong, Rong ; Sternberg, Rachel ; Yang, Xujuan ; Dobrucki, Lawrence W. ; Borst, Luke B. ; Kamstock, Debra ; Song, Ziyuan ; Helferich, William G. ; Cheng, Jianjun ; Fan, Timothy M. / Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 32. pp. E4601-E4609.
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AU - Yin, Qian

AU - Tang, Li

AU - Cai, Kaimin

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AU - Sternberg, Rachel

AU - Yang, Xujuan

AU - Dobrucki, Lawrence W.

AU - Borst, Luke B.

AU - Kamstock, Debra

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AU - Helferich, William G.

AU - Cheng, Jianjun

AU - Fan, Timothy M.

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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.

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