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Published on: June 13, 2014
Pamidronate functionalized nanoconjugates for targeted therapy of focal skeletal malignant osteolysis
Qian Yin1, Li Tang1, Kaimin Cai1
1Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
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.
Insights
Researchers developed targeted nanoparticles loaded with doxorubicin (Doxo) and coated with pamidronate (Pam) for bone cancer. These Pam-Doxo-NPs show enhanced accumulation in bone tumors and reduced osteosarcoma progression in preclinical models and naturally occurring canine tumors.
Area of Science:
- Nanomedicine
- Oncology
- Biomaterials
Background:
- Malignant osteolysis from bone tumors and metastases is a significant clinical challenge.
- Nanomedicine offers a potential strategy for targeted drug delivery to skeletal cancers.
Purpose of the Study:
- To develop and evaluate polylactide nanoparticles (NPs) loaded with doxorubicin (Doxo) and functionalized with bone-seeking pamidronate (Pam) for targeted treatment of malignant skeletal tumors.
Main Methods:
- Development of polylactide nanoparticles loaded with doxorubicin and coated with pamidronate (Pam-Doxo-NPs).
- In vivo biodistribution studies using radiolabeled NPs in murine models.
- Evaluation of therapeutic efficacy in a murine model of osteosarcoma (OS).
- Assessment of safety and efficacy in dogs with naturally occurring OS.
Main Results:
- Targeted Pam-NPs showed enhanced accumulation and retention in bone tumors compared to non-targeted NPs.
- Pam-Doxo-NPs significantly reduced osteosarcoma progression in mice.
- Pam-Doxo-NPs were well-tolerated in dogs with naturally occurring OS, showing no significant toxicities.
- Nuclear scintigraphy confirmed bone-targeting capability, and histopathology showed anticancer activity in canine tumors.
Conclusions:
- Pam-Doxo-NPs represent a promising targeted nanomedicine approach for treating malignant skeletal tumors.
- The study provides the first evaluation of Pam-Doxo-NPs in a large animal model (dogs) with naturally occurring OS, demonstrating safety and efficacy.
- Targeted delivery of doxorubicin via pamidronate-functionalized nanoparticles offers a potential therapeutic strategy for challenging bone cancers.
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