Bone-Targeted PAMAM Nanoparticle to Treat Bone Metastases of Lung Cancer

Abstract

Aim: To prepare pH-sensitive nanoparticle composed of alendronate (ALN) and poly(amidoamine) (PAMAM) to treat bone metastases of lung cancer. Methods: The solvent evaporation method was used to prepare docetaxel (DTX)-loaded ALN-PAMAM nanoparticles (DTX@ALN-PAMAM). Results: The in vitro results showed DTX@ALN-PAMAM significantly enhanced the anticancer activity of DTX and inhibited the formation of osteoclasts. DTX@ALN-PAMAM concentrated at bone metastasis site in mice, which resulted in the suppression of bone resorption, pain response and growth of bone metastases. Eventually, the therapeutic effect of DTX on bone metastases of lung cancer was obviously improved. Conclusion: ALN modified PAMAM nanoparticle could be an effective platform for the treatment of bone metastases of lung cancer.

Alendronate/cRGD-Decorated Ultrafine Hyaluronate Dot Targeting Bone Metastasis

“…Figure 3 shows the hydroxyapatite binding affinity of each dHA sample and (ALN/cRGD)@HDOC-Ce6 NP. First, dHA-Ce6 and (cRGD)@dHA-Ce6 without ALN showed a relatively low 35–40 wt.% nonspecific binding affinity after 180 min, while (ALN)@dHA-Ce6, (ALN/cRGD)@HDOC-Ce6 NP, and (ALN/cRGD)@dHA-Ce6 showed increased binding affinity equivalent to approximately 80 wt.%, probably owing to Ca 2+ (bone)-mediated electrostatic interaction with ALN [ 25 , 26 , 27 ]. These results indicate that dHA samples with ALN have enhanced bone-targeting ability.…”

“…The cells growing on collagen gel with hydroxyapatite particles were treated with dHA samples (equivalent Ce6 10 μg/mL), (ALN/cRGD)@HDOC-Ce6 NP (equivalent Ce6 10 μg/mL), and free Ce6 (10 μg/mL) for 4 h, irradiated using a 670 nm laser source (5.2 mW/cm 2 for 10 min), and then further incubated for 12 h. Subsequently, cell viability was evaluated using a CCK-8 assay. As shown in Figure 4 a, (ALN/cRGD)@dHA-Ce6 exhibited highly increased MDA-MB-231 cell death, probably owing to their efficient binding ability to CD44 receptors, integrin α v β 3 , and hydroxyapatite particles because of the presence of HA, cRGD, and ALN moieties [ 4 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. However, the (ALN/cRGD)@HDOC-Ce6 NP resulted in relatively low phototoxicity to MDA-MB-231 cells because of their reduced cellular uptakes, probably owing to their relatively large particle size.…”

“…To evaluate the photodynamic antitumor efficacy of each sample using a bone metastasis model, BALB/c nude mice were euthanized using carbon dioxide asphyxiation, and their tibias were extracted under sterile conditions. The separated tibias were placed into 6-well plates and incubated with MDA-MB-231 tumor cells (1 × 10 6 cells/mL) in RPMI-1640 medium at 37 °C for 48 h [ 27 , 47 ]. The tibias with MDA-MB-231 tumor cells were incubated with each dHA sample (equivalent Ce6 10 μg/mL), (ALN/cRGD)@HDOC-Ce6 NP (equivalent Ce6 10 μg/mL), and free Ce6 (10 μg/mL) at 37 °C for 4 h, washed three times with PBS (pH 7.4, 150 mM), and then irradiated using a 670 nm laser source (5.2 mW/cm 2 for 10 min).…”

“…The treated cells on tibias were further incubated at 37 °C for 12 h and then fixed using glutaraldehyde, ethanol, and HMDS. The resulting tibias were monitored using a scanning electron microscopy (SEM, S-4800, Hitachi, Tokyo, Japan) [ 27 , 47 ].…”

“…Actually, conventional antitumor drugs are significantly limited in penetration into bone-metastasized tumor tissues owing to the conventional densely packed metastatic tumor tissues in bone regions [ 19 , 20 , 21 , 22 ]. However, it is interesting to note that bisphosphonate drugs inducing apoptosis in osteoclasts and inhibiting osteolysis have shown their potential in high interaction with bone tissues owing to their high affinity (e.g., electrostatic interaction) for bone hydroxyapatite, revealing their attractive role as bone-specific ligands [ 23 , 24 , 25 , 26 , 27 ]. Furthermore, it is also known that hyaluronic acid (HA), a linear biodegradable polysaccharide, can specifically interact with CD44 receptors overexpressed on various metastatic tumors [ 28 , 29 , 30 , 31 , 32 ].…”