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

Abstract

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.

Two Gracilioethers Containing a [2(5H)-Furanylidene]ethanoate Moiety and 9,10-Dihydroplakortone G: New Polyketides from the Caribbean Marine Sponge Plakortis halichondrioides

“…8) and plakortone G (9), respectively. These findings demonstrate that the title compounds do not display significant cytotoxicity effects against MCF-7 cells when compared with letrozole (10) (positive control, IC50 = 20 μM) [27], a drug that is usually prescribed for the treatment of estrogen receptor-positive (ER-positive) breast cancer subtypes, represented here by MCF-7 cells [34].…”

“…For instance, 2,2-bis(6 ′ -bromo-3 ′ -indolyl)ethylamine ( 11), an alkaloid that was isolated for the first time from the marine tunicate Didemnum candidum [43] and later reisolated from the marine sponge Gellius sp., demonstrated an IC 50 of 3.4 µM against MCF-7 cells [44]. The natural marine products depicted in Figure 6, which include alkaloids such as 2,2-bis(6 ′ -bromo-3 ′ -indolyl)ethylamine (11), kuanoniamine A (12), kuanoniamine C (13), and neopetrosiamine A (14), peptides like microcianamide A (15), microciamide B (16), hemiasterlin A (17), hemiasterlin B (18), and stylissatin B (19), the macrocycle polyketide disctyostatin-1 (20), steroids such as aragusterol A (21) and sterols 22-23, and terpenoids like palaluolol (24), thorectandrol B (25), metachromin U (26), and metachromin (27), were sourced from the research conducted by Hussain et al [45]. These compounds have been spotlighted for their substantial activity against MCF-7 cells.…”

“…The cells were left to rise by 80% of confluency and appropriated to perform the cell viability experiments. This cell culture method was adapted from the ATCC product information and other previous works [26,27].…”

“…The experiments were performed in triplicate, and the mean, standard deviation, and coefficient of variation (%CV) were reported. This cell viability assay was adapted from previous studies [26,27].…”

Structural Diversity in Antiosteolytic Bisphosphonates: Deciphering Structure–Activity Trends in Ultra Long Controlled Release Phenomena

“…Almeida Paz et al have studied metal-alendronate coordination polymer-based systems . López-Mejías and colleagues have published several papers on the release of BPs from metal-BP compounds targeted to treat osteolytic metastases, where the metal is a bioactive metal ion (Ca 2+ , Mg 2+ , or Zn 2+ ) and the BP is zoledronate, risedronate, alendronate, or BP analogs. , BP analogs (but not drugs, e.g. p -xylylenebisphosphonate) have been incorporated into coordination polymer backbones containing Ca 2+ and/or Sr 2+ as potential promoters of mineral formation .…”