Abstract
BackgroundThe toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (β-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis.ResultsThe generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis.ConclusionCollectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.Graphic
Highlights
The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application
The synthesis of Hyaluronic acid-Vitamin E succinate (HA-vitamin E succinate (VE)) conjugate was confirmed by 1H nuclear magnetic resonance (NMR) analysis
The chemical structures of these intermediates, including 4-amino-1-butanol, 1,6-hexanediol diacrylate (HDD), and N, N′-bis(acryloyl) cystamine (BACy), and the synthesized PBAEss copolymer were characterized by 1H NMR spectra (Fig. 1d)
Summary
The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. TPL processes substantial anticancer effects against a wide range of cancers [5, 6] with several signaling pathways involved, including those involved in cell apoptosis and in inhibition of cell proliferation and suppression of tumor metastasis [7]. Despite these anticancer benefits, several challenges remain, including the well-acknowledged high toxicity [8], poor solubility, and limited drug delivery efficiency to tumor sites that have severely impeded the potential clinical value of TPL. The polymer-/ligand-drug conjugates are apt to confront the rapid clearance or premature drug release in the blood circulation
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