Hierarchically targetable fiber rods decorated with dual targeting ligands and detachable zwitterionic coronas

The shapes of drug carriers have significant effects on the drug's blood circulation lifetime and tumor accumulation levels. In this study, nonspherical drug carriers of fiber rods are enhanced with hierarchically targeting capabilities to achieve long circulation in blood, on-demand recovery of cell targeting ligands in tumor tissues and dual ligands-mediated cellular uptake. Zwitterionic polymers are conjugated on fiber rods via acid-labile linkers as stealth coronas to reduce the capture by macrophages and shield the targeting ligands. Compared with commonly used poly(ethylene glycol), the zwitterionic grafts show significantly higher inhibition of protein adsorption and lower internalization by macrophages, leading to around 2 folds longer blood circulation and over 2.5 folds higher drug accumulation in tumors than pristine fiber rods. To address the conflicts between blood circulation and cellular uptake, the zwitterionic coronas are efficiently removed in the slightly acidic tumor microenvironment. The exposure of targeting ligands could activate the internalization by tumor cells, resulting in higher cytotoxicity and tumor accumulation than those with stable linkers. Fiber rods are grafted with dual ligands of folate and biotin, and the optimal ligand densities and ratios are determined to maximize the tumor cell uptake. Compared with other treatment, fiber rods with decorated zwitterionic coronas and acid-liable exposure of dual targeting ligands enhance the suppression of tumor growth, prolong animal survival, and cause less lung metastasis. The development of fiber rods with hierarchically targeting capabilities shows great potential in improving the blood circulation, tumor accumulation and cellular uptake, and eventually promoting therapeutic efficacy. STATEMENT OF SIGNIFICANCE: The targeted delivery of chemotherapeutic agents will encounter a series of biological and pathological barriers. In this study, fiber rods were empowered with hierarchically targeting capabilities to resolve the conflict between blood circulation and cellular uptake. This strategy has shown several advantages over the existing methods. Firstly, zwitterionic polymers were used as blood circulation ligands, and concrete evidence was provided via head-to-head comparison with commonly used poly(ethylene glycol) ligands in the macrophage uptake and in vivo tissue distribution. Secondly, the depletion of circulation ligands and on-demand exposure of targeting ligands in tumor tissues showed crucial effects on the uptake by tumor cells. Thirdly, the densities and ratios of the dual targeting ligands were initially determined for a maximal cellular internalization.