High-Affinity Extended Bisphosphonate-Based Coordination Polymers as Promising Candidates for Bone-Targeted Drug Delivery

Extended bisphosphonate-based coordination polymers (BPCPs)
were
produced when 1,1′-biphenyl-4,4′-bisphosphonic acid
(BPBPA), the analogue of 1,1′-biphenyl-4,4′-dicarboxylic
acid (BPDC), reacted with bioactive metals (Ca2+, Zn2+, and Mg2+). BPBPA-Ca (11 Å × 12 Å),
BPBPA-Zn (10 Å × 13 Å), and BPBPA-Mg (8 Å ×
11 Å) possess channels that allow the encapsulation of letrozole
(LET), an antineoplastic drug that combined with BPs treats breast-cancer-induced
osteolytic metastases (OM). Dissolution curves obtained in phosphate-buffered
saline (PBS) and fasted-state simulated gastric fluid (FaSSGF) demonstrate
the pH-dependent degradation of BPCPs. Specifically, the results show
that the structure of BPBPA-Ca is preserved in PBS (∼10% release
of BPBPA) and collapses in FaSSGF. Moreover, the phase inversion temperature
nanoemulsion method yielded nano-Ca@BPBPA (∼160
d. nm), a material with measurably higher (>1.5x)
binding to hydroxyapatite than commercial BPs. Furthermore, it was
found that the amounts of LET encapsulated and released (∼20
wt %) from BPBPA-Ca and nano-Ca@BPBPA are comparable
to those of BPDC-based CPs [i.e., UiO-67-(NH2)2, BPDC-Zr, and bio-MOF-1], where other antineoplastic drugs have
been loaded and released under similar conditions. Cell viability
assays show that, at 12.5 μM, the drug-loaded nano-Ca@BPBPA exhibits higher cytotoxicity against breast cancer cells
MCF-7 and MDA-MB-231 [relative cell viability (%RCV) = 20 ± 1
and 45 ± 4%] compared with LET (%RCV = 70 ± 1 and 99 ±
1%). At this concentration, no significant cytotoxicity was found
for the hFOB 1.19 cells treated with drug-loaded nano-Ca@BPBPA and LET (%RCV = 100 ± 1%). Collectively, these results
demonstrate the potential of nano-Ca@BPCPs as promising
drug-delivery systems to treat OM or other bone-related diseases because
these present measurably higher affinity, allowing bone-targeted drug
delivery under acidic environments and effecting cytotoxicity on estrogen
receptor-positive and triple-negative breast cancer cell lines known
to induce bone metastases, without significantly affecting normal
osteoblasts at the metastatic site.