Design of Extended Bisphosphonate-Based Coordination Polymers as Bone-Targeted Drug Delivery Systems for Breast Cancer-Induced Osteolytic Metastasis and Other Bone Therapies

Extended bisphosphonate-basedcoordination polymers (BPCPs)present higher binding (>2.5x) than commercialBPsto the main constituent of bone, comparable drug loading/release (similar to 30wt % 5-fluorouracil) relative to other network coordination polymers(i.e., MIL-53), and the ability to effect cytotoxicity against a triple-negativehuman breast cancer cell line (MDA-MB-231) known to metastasize tothe bone without disrupting viability in human osteoblast-like hFOB1.19 cells. Collectively, these results demonstrate the potentialof BPCPs as bone-targeted drug delivery systems to treat bone-relateddiseases such as osteolytic metastases. The coordination between benzene 1,4-bis(bisphosphonicacid) (BBPA),the bisphosphonate (BP) analogue of benzene 1,4-dicarboxylic acid(BDC), and bioactive metals led to the formation of extended bisphosphonate-basedcoordination polymers (BPCPs). Four distinct crystalline phases wereobtained, namely, BBPA-Ca forms I and II, BBPA-Zn, and BBPA-Mg. Amongthese, BBPA-Ca forms I (7 x 9 angstrom(2)) and II (8 x12 angstrom(2)) possess channels large enough to encapsulate5-fluorouracil (5-FU), a drug prescribed in combination with BPs totreat breast cancer-induced osteolytic metastases (OM). Dissolutioncurves show a 14% release of BBPA from BBPA-Ca form II in phosphate-bufferedsaline, while similar to 90% was released in fasted-state simulated gastricfluid. These results suggest that this material is relatively stablein neutral environments yet collapses in acidic conditions. Moreover,the phase inversion temperature method decreased the particle sizeof BBPA-Ca form II, resulting in nano-Ca@BBPA (similar to 134 d.nm).Binding assays showed a higher affinity of nano-Ca@BBPA (similar to 97%)to hydroxyapatite than BBPA (similar to 70%) and significantly higherbinding than commercial BPs, zolendronic (3.0x), and risedronic(2.4x) acids after 24 h. Furthermore, both BBPA-Ca form II andnano-Ca@BBPA presented comparable drug loading and release (similar to 30wt % 5-FU) relative to BDC-based CCs (UiO-66, MIL-53, and BDC-Zr)where other pharmaceutical compounds (caffeine, ibuprofen, aspirin,and alpha-cyano-4-hydroxycinnamic acid) have been encapsulated.Cell viability assays established that drug-loaded nano-Ca@BBPA increasesthe cytotoxicity of a triple-negative human breast cancer cell line(MDA-MB-231) when compared to 5-FU (%RCV = 8 +/- 5 vs 75 +/- 1% at a 100 mu M). At the same concentration, no significant decreasein cell viability was observed for normal human osteoblast-like hFOB1.19 cells (%RCV = 85 +/- 1%). Collectively, these results demonstratethe feasibility of nano-Ca@BBPA as a potential drug delivery system(DDS), with high affinity to bone tissue, to treat bone-related diseasessuch as OM.