Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Genome of Plant Maca （Lepidium meyenil） Illuminates Genomic Basis for High-Altitude Adaptation in the Central Andes

Maca （Lepidium meyenii Walp, 2n = 8x = 64）, belonging to the Brassicaceae family, is an economic plant cultivated in the central Andes sierra in Peru （4000-4500 m）. Considering that the rapid uplift of the central Andes occurred 5-10 million years ago （Ma）, an evolutionary question arises regarding how plants such as maca acquire high-altitude adaptation within a short geological period. Here, we report the high-quality genome assembly of maca, in which two closely spaced maca-specific whole-genome duplications （WGDs; ~6.7 Ma） were identified. Comparative genomic analysis between maca and closely related Brassicaceae species revealed expansions of maca genes and gene families involved in abiotic stress response, hormone signaling pathway, and secondary metabolite biosynthesis via WGDs. The retention and subsequent functional divergence of many duplicated genes may account for the morphological and physiological changes （i.e., small leaf shape and self-fertility） in maca in a high-altitude environment. In addition, some duplicated maca genes were identified with functions in morphological adaptation （i.e., LEAF CURLING RESPONSIVENESS） and abiotic stress response （i.e., GL YClNE-RICH RNA-BINDING PROTEINS and DNA-DAMAGE-REPAIR/TOLERATION2） under positive selection. Collectively, the maca genome provides use- ful information to understand the important roles of WGDs in the high-altitude adaptation of plants in the Andes.