Unforeseen consequences of synergizing PEGylated rapamycin and quercetin in angiogenesis and metastasis inhibition: Turning failure into benefit

Cancer continues to be a significant health hazard to the patient’s body around the globe, with more than 19 million incidents in 2020 worldwide, according to the world health organization, and it is expected to surpass 30 million in 2040. The advancement of nanomedicine focuses on enhancing the anticancer drugs that suffer from poor water solubility, unspecific cytotoxicity, and unfavorable pharmacokinetic properties. The most promising nanocarriers would be biodegradable and biocompatible, making the anticancer drugs soluble, preventing their aggregation, and enabling site-specific targeting. Herein, we formulated a rational design of two anticancer drugs (PEGylated rapamycin and quercetin) in a single micellar nanosystem, the ideal nanocarrier for water-insoluble drugs. After encapsulation, cytotoxicity and cellular uptake were increased. The quercetin loaded PEGylated rapamycin micelles (QRPM) exhibited significantly higher in vitro cytotoxicity in breast cancer cells than free drugs, mainly because of higher cellular uptake achieved via micelles. Moreover, the pharmacodynamic investigations indicated that QRPM significantly inhibited tumor growth compared to free drugs and PEGylated rapamycin micelles. Generally, QRPM could dramatically enhance the antitumor activity. They might be a promising drug delivery platform for anti-angiogenesis, -migration, and -invasion therapy as the nanosystem dramatically inhibited them compared with free drugs.