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Dual targeted zeolitic imidazolate framework nanoparticles for treating metastatic breast cancer and inhibiting bone
1Mechanobiology and Regenerative Medicine Laboratory, Bioengineering College, Chongqing University, Chongqing 400044, China.
Abstract:
Tumor bone metastasis is still difficult to cure despite the development of various treatment strategies. Drug delivery systems can improve the poor biological distribution of anticancer drugs in tumors. But only a very small number of nanoparticles can cross the physiological barrier to reach the tumor. In addition, the progression of bone metastasis is influenced by tumor cells, osteoclasts and bone matrix. To address these problems, a bone and tumor dual targeted nanocarrier was developed by utilizing NF-κB inhibitor loaded into zeolitic imidazolate framework-8 (ZIF-8) (CZ), which was then coated with hyaluronic acid/alendronate (HA/ALN). The CZ prepared by two-step method had high loading capacity, and the loading efficiency of Cur was to be 47.55 ± 4.03%. HA/ALN functionalization avoided explosive release of reagents and improved the stability of nanoparticles. The dual targeted ZIF-8 nanoparticle (CZ@HA/ALN) had a pH-triggered drug release performance, which effectively inhibited breast cancer cells growth and osteoclastogenesis in vitro. Uptake experiments showed that the conjugation of ALN with HA did not affect targeting ability of HA. Moreover, HA/ALN functionalized nanoparticles were more aggregated at bone metastasis sites than HA functionalized nanoparticles. CZ@HA/ALN could block the PD-1 immune check point, leading to Raw 264.7 cells differentiation into anti-tumor macrophage rather than osteoclast. The antitumor experiments in vivo exhibited that the dual targeted ZIF-8 nanoparticle effectively inhibited bone resorption and tumor progress, thereby improving the bone microenvironment. Therefore, this single but versatile nanoparticle provided a promising therapeutic scheme for bone metastasis treatment.
Insights
A novel dual-targeted nanoparticle effectively treats bone metastasis by inhibiting tumor growth and osteoclast activity. This nanocarrier improves drug delivery to bone tumors, enhancing the bone microenvironment for better therapeutic outcomes.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Bone metastasis remains a significant clinical challenge despite advancements in cancer therapy.
- Conventional treatments suffer from poor drug distribution and limited efficacy at tumor sites.
- The progression of bone metastasis involves complex interactions between tumor cells, osteoclasts, and the bone matrix.
Purpose of the Study:
- To develop a dual-targeted nanocarrier for enhanced treatment of bone metastasis.
- To improve the delivery and efficacy of anticancer drugs to bone tumor microenvironments.
- To investigate the therapeutic potential of NF-κB inhibitor-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles functionalized with hyaluronic acid/alendronate (HA/ALN).
Main Methods:
- Synthesized NF-κB inhibitor-loaded ZIF-8 nanoparticles (CZ) via a two-step method.
- Functionalized CZ nanoparticles with hyaluronic acid and alendronate (CZ@HA/ALN) for dual targeting.
- Evaluated nanoparticle characteristics, drug loading, stability, and pH-triggered release.
- Assessed in vitro inhibition of breast cancer cells and osteoclastogenesis.
- Investigated nanoparticle aggregation at bone metastasis sites and PD-1 immune checkpoint blockade.
- Conducted in vivo antitumor experiments to evaluate efficacy in inhibiting bone resorption and tumor progression.
Main Results:
- High drug loading capacity (47.55 ± 4.03% for Curcumin) and improved nanoparticle stability were achieved.
- CZ@HA/ALN nanoparticles demonstrated pH-triggered drug release, effectively inhibiting cancer cell growth and osteoclastogenesis in vitro.
- HA/ALN functionalization enhanced nanoparticle aggregation at bone metastasis sites without compromising targeting ability.
- Nanoparticles blocked the PD-1 immune checkpoint, promoting anti-tumor macrophage differentiation over osteoclastogenesis.
- In vivo studies showed significant inhibition of bone resorption and tumor progression, leading to improved bone microenvironment.
Conclusions:
- The developed dual-targeted ZIF-8 nanoparticle (CZ@HA/ALN) offers a promising therapeutic strategy for bone metastasis.
- This nanocarrier system effectively targets bone and tumor sites, enhances drug delivery, and modulates the immune microenvironment.
- The findings suggest a versatile nanoparticle platform for improving treatment outcomes in bone metastasis.
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