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

Extended bisphosphonate-based coordination polymers (BPCPs)wereproduced when 1,1 & PRIME;-biphenyl-4,4 & PRIME;-bisphosphonic acid(BPBPA), the analogue of 1,1 & PRIME;-biphenyl-4,4 & PRIME;-dicarboxylicacid (BPDC), reacted with bioactive metals (Ca2+, Zn2+, and Mg2+). BPBPA-Ca (11 & ANGS; x 12 & ANGS;),BPBPA-Zn (10 & ANGS; x 13 & ANGS;), and BPBPA-Mg (8 & ANGS; x11 & ANGS;) possess channels that allow the encapsulation of letrozole(LET), an antineoplastic drug that combined with BPs treats breast-cancer-inducedosteolytic metastases (OM). Dissolution curves obtained in phosphate-bufferedsaline (PBS) and fasted-state simulated gastric fluid (FaSSGF) demonstratethe pH-dependent degradation of BPCPs. Specifically, the results showthat the structure of BPBPA-Ca is preserved in PBS (& SIM;10% releaseof BPBPA) and collapses in FaSSGF. Moreover, the phase inversion temperaturenanoemulsion method yielded nano-Ca@BPBPA (& SIM;160d. nm), a material with measurably higher (>1.5x)binding to hydroxyapatite than commercial BPs. Furthermore, it wasfound that the amounts of LET encapsulated and released (& SIM;20wt %) from BPBPA-Ca and nano-Ca@BPBPA are comparableto those of BPDC-based CPs [i.e., UiO-67-(NH2)(2), BPDC-Zr, and bio-MOF-1], where other antineoplastic drugs havebeen loaded and released under similar conditions. Cell viabilityassays show that, at 12.5 & mu;M, the drug-loaded nano-Ca@BPBPA exhibits higher cytotoxicity against breast cancer cellsMCF-7 and MDA-MB-231 [relative cell viability (%RCV) = 20 & PLUSMN; 1and 45 & PLUSMN; 4%] compared with LET (%RCV = 70 & PLUSMN; 1 and 99 & PLUSMN;1%). At this concentration, no significant cytotoxicity was foundfor the hFOB 1.19 cells treated with drug-loaded nano-Ca@BPBPA and LET (%RCV = 100 & PLUSMN; 1%). Collectively, these resultsdemonstrate the potential of nano-Ca@BPCPs as promisingdrug-delivery systems to treat OM or other bone-related diseases becausethese present measurably higher affinity, allowing bone-targeted drugdelivery under acidic environments and effecting cytotoxicity on estrogenreceptor-positive and triple-negative breast cancer cell lines knownto induce bone metastases, without significantly affecting normalosteoblasts at the metastatic site.