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Abstract
Paclitaxel (PTX), especially albumin-bound PTX in clinical, has displayed significant inhibition of tumor growth in patients. But the systemic distribution and poor water solubility of PTX often lead to severe side effects, consequently limiting the anti-tumor efficacy. In this study, we developed a novel PTX-loaded polymeric micelle drug delivery system. These self-assembled polymeric micelles from core to outside consisted of poly L-phenylalanine (pPhe), DTSSP linked poly L-lysine (pLys), poly ethylene glycol (PEG) and dehydroascorbic acids (DHA). pPhe formed the hydrophobic core to encapsulate PTX; DTSSPs on pLys covalently cross-linked and formed disulfide bond to stabilize PTX from loss in blood circulation; PEG improved solubility to lower toxicity of PTX for its high hydrophilicity; DHA targeted tumors by specifically recognizing GLUT1 mainly expressed on tumor cells. Thus, PTX would be precisely released into tumor cells with high dose of glutathione to break disulfide bond. Moreover, these PTX-loaded polymer micelles significantly suppressed tumor cell viability, proliferation, and migration in vitro, and also greatly inhibited tumor growth and prolonged survival in tumor-bearing mice without detectable side effects. Therefore, the new drug delivery system could reduce severe side effects and enhance anti-tumor efficacy of PTX via peripheral stabilization, low toxicity and tumor targeting.
Highlights
Ethanol have served as solvents to enhance its solubility
We developed a novel PTX delivery system, which consisted of polymeric micelles modified by poly ethylene glycol (PEG) to improve solubility, Dehydroascorbic acid (DHA) to target tumors and disulfide bond covalent cross-link to stabilize PTX in blood circulation (Fig. 1)
The Mn of N3-PEG-poly L-lysine (pLys)-poly L-phenylalanine (pPhe) and DHA-PEGpLys-pPhe calculated by Gel permeation chromatography (GPC) analyses were 11,300 g/mol and 12,100 g/mol, respectively
Summary
Ethanol have served as solvents to enhance its solubility. The solution needs to be further diluted and filtrated in the solubilizer before used, while the solubilizer polyoxyethylene castor oil may cause the release of histamine, which leads to acute allergic reactions, even death[8]. The hydrophilic shell of polymeric micelles can be grafted with various targeting ligands that recognize cancer cells to further enhance the active targeting and cellular internalization. Often employed to functionalize the polymeric micelles for active tumor targeting[14, 15] It has a high affinity for glucose transport protein 1 (GLUT1)[16, 17], which is selectively over-expressed on the surface of hepatic carcinoma cells (HepG2) and colon cancer cells (SW480)[16, 18,19,20,21,22,23]. The disulfide bond covalent cross-linking could enhance the stability of polymeric micelles in blood circulation and prevent drug unnecessary loss[25, 26]. We developed a novel PTX delivery system, which consisted of polymeric micelles modified by PEG to improve solubility, DHA to target tumors and disulfide bond covalent cross-link to stabilize PTX in blood circulation (Fig. 1). Our system might facilitate the clinical use of nano-carriers such as polymeric micelles in conquering cancers and other critical diseases
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