Alendronate/cRGD-Decorated Ultrafine Hyaluronate Dot Targeting Bone Metastasis

Abstract

In this study, we report the hyaluronate dot (dHA) with multiligand targeting ability and a photosensitizing antitumor model drug for treating metastatic bone tumors. Here, the dHA was chemically conjugated with alendronate (ALN, as a specific ligand to bone), cyclic arginine-glycine-aspartic acid (cRGD, as a specific ligand to tumor integrin αvβ3), and photosensitizing chlorin e6 (Ce6, for photodynamic tumor therapy), denoted as (ALN/cRGD)@dHA-Ce6. These dots thus prepared (≈10 nm in diameter) enabled extensive cellular interactions such as hyaluronate (HA)-mediated CD44 receptor binding, ALN-mediated bone targeting, and cRGD-mediated tumor integrin αvβ3 binding, thus improving their tumor targeting efficiency, especially for metastasized MDA-MB-231 tumors. As a result, these dots improved the tumor targeting efficiency and tumor cell permeability in a metastatic in vivo tumor model. Indeed, we demonstrated that (ALN/cRGD)@dHA-Ce6 considerably increased photodynamic tumor ablation, the extent of which is superior to that of the tumor ablation of dot systems with single or double ligands. These results indicate that dHA with multiligand can provide an effective treatment strategy for metastatic bone tumors.

Endosomal pH-Responsive Fe-Based Hyaluronate Nanoparticles for Doxorubicin Delivery

“…The quantitative cellular uptake of the DOX-loaded Fe-based HA NPs was measured using a flow cytometer. As shown in Figure 3a, the average fluorescent DOX intensity observed in MDA-MB-231 cells (with CD44 receptors) [11,31] was ~8.3 × 10 3 (free DOX), ~7.9 × 10 2 (DOX@HA/Fe NPs), ~8.1 × 10 2 (DOX@aHA-DMA 0.36 /Fe NPs), and ~9.3 × 10 2 (DOX@aHA-DMA 0.60 /Fe NPs). However, the DOX@HA/Fe NPs, DOX@aHA-DMA 0.36 /Fe NPs, and DOX@aHA-DMA 0.60 /Fe NPs showed low cellular internalization in Huh7 cells (without CD44 receptors) (Figure 3b) [11].…”

“…)/0.03% (wt./vol.)). The collected cells (1 × 10 6 cells/mL) were seeded into a 96-well culture plate and cultured in RPMI-1640 medium for 24 h [11,[18][19][20]31,32].…”

“…The NPs (equivalent to DOX 10 µg/mL) or free DOX (10 µg/mL) suspended in an RPMI-1640 medium (pH 7.4 or 6.8) were incubated with MDA-MB-231 cells (CD44 receptorpositive cells) and Huh7 cells (CD44 receptor-negative cells) at 37 • C for 4 h. The treated cells were washed three times with fresh PBS (pH 7.4). The DOX fluorescence intensity (λ ex of 470 nm and λ em of 592 nm) of the treated cells was analyzed using a flow cytometer (FACS Calibur, Becton Dickinson, Franklin Lakes, NJ, USA) [11,17,31].…”

“…All data were evaluated using Student's t-test or analysis of variance (ANOVA) at a significance level of p < 0.01 (**) [18][19][20][21][22][27][28][29][30][31][32].…”

Progress of Phototherapy Applications in the Treatment of Bone Cancer

“…The multiligand targeting ability was verified by the strong Ce6 fluorescence signal ( Figure 2 ). The bone metastasis in mice caused by human breast carcinoma (MDA-MB-231) cells was inhibited using PDT based on this novel PS [ 106 ]. The nanoformulation with targeted recognition technology has the potential for improving the tumor-targeting efficiency of PSs.…”