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Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy.

ABSTRACT: Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as carriers increases the water-solubility of paclitaxel by 32,000-fold. Intravenous injections of RNA-paclitaxel nanoparticles with specific cancer-targeting ligand dramatically inhibit breast cancer growth, with nearly undetectable toxicity and immune responses in mice. No fatalities are observed at a paclitaxel dose equal to the reported LD50. The use of ultra-thermostable RNA nanoparticles to deliver chemical prodrugs addresses issues with RNA unfolding and nanoparticle dissociation after high-density drug loading. This finding provides a stable nano-platform for chemo-drug delivery as well as an efficient method to solubilize hydrophobic drugs.

SUBMITTER: Guo S

PROVIDER: S-EPMC7033104 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy.

Guo Sijin S Vieweger Mario M Zhang Kaiming K Yin Hongran H Wang Hongzhi H Li Xin X Li Shanshan S Hu Shuiying S Sparreboom Alex A Evers B Mark BM Dong Yizhou Y Chiu Wah W Guo Peixuan P

Nature communications 20200220 1

Paclitaxel is widely used in cancer treatments, but poor water-solubility and toxicity raise serious concerns. Here we report an RNA four-way junction nanoparticle with ultra-thermodynamic stability to solubilize and load paclitaxel for targeted cancer therapy. Each RNA nanoparticle covalently loads twenty-four paclitaxel molecules as a prodrug. The RNA-paclitaxel complex is structurally rigid and stable, demonstrated by the sub-nanometer resolution imaging of cryo-EM. Using RNA nanoparticles as ...[more]

PMID: 32080195

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Project description:Nanomaterials have been well demonstrated to have the potential to be used for tumor cell-targeted drug delivery. Targeted inhibition of miR-221 was proved to promote the sensitivity of triple genitive breast cancer (TNBC) cells to chemo-drugs. In order to improve the chemotherapeutic effect in TNBC, herein, we developed a novel kind of nanoparticles shelled with PLGA and loaded with perfluoropentane (PFP), paclitaxel (PTX), and anti-miR-221 inhibitor, which was named PANP. Ultrasound-triggered vaporization of PFP in PANPs was utilized for real-time imaging track of the nanoparticles in vivo. In addition, macrophages were applied for the internalization of PANPs to form RAW-PANP with strong chemotaxis to accumulate around cancer cells. Nanoparticles with different contents did not cause M2 polarization compared with the control group but caused polarization toward M1. We compared the inherent tumor-homing behavior of macrophages containing different contents with that of normal macrophages and no significant abnormalities were observed. After injection into the tumor-burden mice, RAW-PANPs showed enrichment within tumor tissues. Upon the ultrasound cavitation-triggered burst, PTX was released in the tumor. Meanwhile, the release of anti-miR-221 improved the sensitivity of tumor cells to PTX. As a result, RAW-PANPs showed high efficiency in suppressing TNBC cell proliferation in vitro and inhibiting tumor growth and progression in vivo. The treatments did not induce liver, heart, or kidney injury. In conclusion, the current study not only developed a macrophage-carried, ultrasound-triggered, cancer cell-targeted chemotherapeutic system, but also demonstrated a miRNA-based technique to promote drug sensitivity of cancer cells, which holds strong potential to treat patients with TNBC, especially for those suffering drug-resistance. The innovation of this study is to use macrophages to deliver nanoparticles to the tumors and then use ultrasound locally to burst the nanoparticles to release the miRNA and PTX.

Project description:Background:Melanoma is the most common symptom of aggressive skin cancer, and it has become a serious health concern worldwide in recent years. The metastasis rate of malignant melanoma remains high, and it is highly difficult to cure with the currently available treatment options. Effective yet safe therapeutic options are still lacking. Alternative treatment options are in great demand to improve the therapeutic outcome against advanced melanoma. This study aimed to develop albumin nanoparticles (ANPs) coated with macrophage plasma membranes (RANPs) loaded with paclitaxel (PTX) to achieve targeted therapy against malignant melanoma. Methods:Membrane derivations were achieved by using a combination of hypotonic lysis, mechanical membrane fragmentation, and differential centrifugation to empty the harvested cells of their intracellular contents. The collected membrane was then physically extruded through a 400 nm porous polycarbonate membrane to form macrophage cell membrane vesicles. Albumin nanoparticles were prepared through a well-studied nanoprecipitation process. At last, the two components were then coextruded through a 200 nm porous polycarbonate membrane. Results:Using paclitaxel as the model drug, PTX-loaded RANPs displayed significantly enhanced cytotoxicity and apoptosis rates compared to albumin nanoparticles without membrane coating in the murine melanoma cell line B16F10. RANPs also exhibited significantly higher internalization efficiency in B16F10 cells than albumin nanoparticles without a membrane coating. Next, a B16F10 tumor xenograft mouse model was established to explore the biodistribution profiles of RANPs, which showed prolonged blood circulation and selective accumulation at the tumor site. PTX-loaded RANPs also demonstrated greatly improved antitumor efficacy in B16F10 tumor-bearing mouse xenografts. Conclusion:Albumin-based nanoscale delivery systems coated with macrophage plasma membranes offer a highly promising approach to achieve tumor-targeted therapy following systemic administration.

Dataset Information

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy.

Publications

Ultra-thermostable RNA nanoparticles for solubilizing and high-yield loading of paclitaxel for breast cancer therapy.

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