| The rapid clearance of circulating nanocarriers during systemic drug delivery remains a major challenge in cancer chemotherapy. Here inspired by the viruses and bacterial pathogens with various asymmetric geometries have a great capacity of infecting specific cell types; especially those rod-like bacterial pathogens including the Gram-negative bacteria Salmonella and the Gram-positive bacterium Listeria monocytogenes can induce their entry into nonphagocytic mammalian cells, we develop biodegradable polymer micelles with a precise control of rod-liked shape for enhanced infecting and killing targeted tumor cells.In this study, we develop the bioinspired rod-shaped polymer micelles by simply changing NaCl solution concentration for improving the drug delivery efficiency and consequently enhancing cancer therapy. The polymer micelles with spherical (S), short rod-like (SR), long rod-like (LR) shapes were formed by the self-assembly of amphiphilic mPEG-PCL copolymers by adjusting the salt solution concentration. The morphology of micelles were characterized by AFM, TEM as well as CLSM. To investigate the influences of both 0.9% physiological saline solution and the storage period on the stability of various shaped micelles, S, SR and LR micelles were added in 0.9% sodium chloride solution, respectively. The stability was studied by DLS at different time point, the mean size and size distribution of S, SR and LR samples represent a negligible change within 120 h, suggesting that a good stability of micelles in 0.9% physiological saline solution. The loading capacity of DOX in LR micelle (LC:8.4±0.45%) is the highest among all these micelles. An approximate zero-order in vitro drug release mode with a fast speed can be achieved in an acid environment similar with that of tumor cells.In vitro cytotoxicity analysis demonstrate that the DOX-loaded short-rod like shape mPEG-CL41 micelles(SR@DOX)are of great efficiency in inhibiting the growth of HeLa/HepG2 cancer cells, and inducing cells apoptosis. To evaluate the effect of micellar shape on cellular uptake efficiency, we found that the bioinspired rod-like micelles have a relatively high uptake efficiency compared to spheres. Integrated and normal micellar structures are seen in TEM ultrathin section samples represent that cellular internalization process won’t impact of micellar morphology. For the internalization pathway, we can conclude that cellular internalization mechanisms for micelles vary significantly with both micelle geometry and cell type-specific. Moreover, the internalization of micelles with various shapes appears to follow multiple pathways.The in vivo pharmacokinetics, biodistribution and tumor growth inhibition are evaluated by the analysis of DOX clearance in the blood, DOX accumulation in tissues, changes of body weight, tumor volume, and tumor weight of tumor-bearing Balb/c mice. All of the micellar DOX formulations can prolong the blood circulation of DOX, especially the LR@DOX possesses the longest circulation. The DOX accumulations of S@DOX, SR@DOX and LR@DOX in tumors were all significantly enhanced in comparison to free DOX, especially at 6,12 and 24 h, which were 7.84-,12.59- and 17.98-fold higher than that in the free DOX group at 24 h, respectively. Both the qualitative and quantitative results of the antitumor activity reveal that the LR@DOX have a more significant therapeutic effect to artificial solid tumor. TUNEL histological analysis of tumor sections also indicated LR@DOX group had the best tumor suppression effect. |
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