A Conjugate of Gemcitabine With Bisphosphonate (Gem/BP) Shows Potential as a Targeted Bone-Specific Therapeutic Agent in an Animal Model of Human Breast Cancer Bone Metastases

Abstract

Bone metastases in advanced breast cancer patients remains a significant treatment challenge. Bisphosphonates are now a routine first line treatment for prevention and treatment of skeletal damage caused by malignancies and, moreover, have shown an ability to transport therapeutic drugs to the bone. Here, we describe the effect of a conjugate between the potent anticancer drug gemcitabine and a bisphosphonate molecule (Gem/BP) in an animal model of breast cancer metastases. We have previously demonstrated the targeting of this compound to bone in normal mice using an analog labeled with the radionuclide 99mTc. Using a bone metastasis model in nude mice produced by intracardiac injection of the human breast cancer cell line MDA-MB-231BO, we examined the effect of Gem/BP and gemcitabine in reducing the frequency and severity of osteolytic bone lesions. High-resolution radiographs and microPET images showed that Gem/ BP reduced the number and size of bone metastases relative to the gemcitabine-treated and the untreated control groups. Histological examination of the humeri and femurs of the control and gemcitabine groups revealed large metastatic cancer lesions in the outer and inner cortices and the medullary cavities. In contrast, Gem/BP-treated mice showed occasional small wedge-shaped metastases under the periosteum of the outer cortex and very occasionally in the medulla. These findings suggest that Gem/BP should be further evaluated for use in the treatment of bone metastases in breast cancer.

In vitro and in vivo toxicity of 5-FdU-alendronate, a novel cytotoxic bone-seeking duplex drug against bone metastasis

“…Recently designed conjugates linking BPs with an antimetabolite [22,23] successfully proved the concept that a BPantimetabolite-conjugate potently enables the targeting of the antimetabolites to the metastatic sites in the bone. The conjugation of etidronate with a cytotoxic 5′-nucleotide analogue via a phosphoanhydrid linkage resulted in nucleoside-5′-triphosphate analogues, in which the ß-and γ-phosphorous atoms are connected via a carbon instead of an oxygen atom [22].…”

“…Yet, the coupling of more active amino-BPs such as ale or zoledronate to an antimetabolite via the phosphoanhydrid linkage remained unsuccessful. A described alternative coupling methylene-BP with gemcitabine via an unnatural urethane linkage is also not possible for amino-BPs conjugations [23]. However, the chemical linkage between BP and the antimetabolite is the key structure element for the therapeutic efficacy of such boneseeking conjugates.…”

Targeted delivery to bone and mineral deposits using bisphosphonate ligands

“…Therefore, future studies need to measure the accumulation of BP-cisplatin conjugates in bone metastases in vivo and compare the therapeutic efficacy of BP-cisplatin versus cisplatin alone, BP alone, and co-delivery of cisplatin and BP alone. Other BP-conjugated chemotherapy agents that have been investigated include BP conjugated to taxanes [95][96][97], platinum complexes [98], camptothecin [99], gemcitabine [49,[100][101][102], doxorubicin [103,104], methotrexate [105], proteasome inhibitors [106,107],…”

Inhibition of bone loss with surface-modulated, drug-loaded nanoparticles in an intraosseous model of prostate cancer

“…A major fraction of the administered drug is either excreted and/or metabolized, often via hepatic processes; or may accumulate in other, more highly perfused body compartments or tissues prior to reaching the marrow in sufficient doses. To overcome this challenge, such approaches as conjugating anticancer drugs [6] or drug-loaded nanoparticles (NPs) to bone-seeking agents (e.g., bisphosphonates [7], tetracycline [8], or E-selectin [overexpressed in bone marrow endothelium] [9]) have been investigated, but these remain inefficient. For example, Wang et al [10] found that bisphosphonate-conjugated to NPs made with bovine serum albumin did not target bone in vivo , despite in vitro results showing that they had significantly higher affinity than unconjugated NPs to hydroxyapatite, a major component of bone.…”