Abstract
Liver fibrosis, originating from activated hepatic stellate cells (HSCs), is receiving much attention in the treatment of clinical liver disease. In this study, mitochondria-targeted curcumin (Cur) loaded 3-carboxypropyl-triphenylphosphonium bromide–poly(ethylene glycol)–poly(ε-caprolactone) (CTPP–PEG–PCL) micelles were constructed to prolong the systemic circulation of Cur, improve the bioavailability of Cur and play a precise role in anti-fibrosis. The prepared Cur–CTPP–PEG–PCL micelles with a spherical shape had satisfactory dispersion, low critical micelle concentration (CMC) and high encapsulation efficiency (92.88%). The CTPP modification endowed good endosomal escape ability to the CTPP–PEG–PCL micelles, and micelles could be selectively accumulated in mitochondria, thereby inducing the enhanced cell proliferation inhibition of HSC-T6 cells. Mitochondrial Membrane Potential (MMP) was greatly reduced due to the mitochondrial-targeting of Cur. Moreover, the system circulation of Cur was extended and bioavailability was significantly enhanced in vivo. As expected, Cur loaded CTPP–PEG–PCL micelles were more effective in improving liver fibrosis compared with Cur and Cur–mPEG–PCL micelles. In conclusion, the Cur–CTPP–PEG–PCL based micelles can be a potential candidate for liver fibrosis treatment in future clinical applications.
Highlights
Liver brosis is a compensatory response of tissue self-repair a er persistent liver damage caused by various pathogenic factors, and it is the most common histopathological change in the development of various chronic liver diseases.[1]
Hepatic Stellate Cells (HSC-T6) and Alpha Mouse Liver 12 (AML12) used in the study were purchased from the American Type Culture Collection (ATCC) and cultured in RPMI 1640 medium supplemented with 10% Fetal bovine serum (FBS) and penicillinstreptomycin (100 IU mLÀ1 to 100 mg mLÀ1) under 5% CO2 atmosphere at 37 C
The Fourier transform infrared spectroscopy (FTIR) spectrum of carboxypropyltriphenylphosphonium bromide (CTPP)–Polyethylene glycol (PEG)–OH was illustrated in Fig. S1.† As shown in the spectrum of CTPP–PEG–OH, 1280.00 cmÀ1 belonged to –C–O–C, 1730.00 cmÀ1 belonged to C]O, 3417.72 cmÀ1 belongs to OH in –CH2–OH, 1600 cmÀ1, 740.84 cmÀ1, 842.28 cmÀ1, 691.78 cmÀ1 were all characteristic peaks of aromatics
Summary
Curcumin is a naturally-occurring polyphenol phytochemical, which possess various pharmacological activities such as antioxidant, anti-in ammatory, and protecting liver function.[13,14,15] Researches have shown that curcumin can signi cantly improve liver brosis, including inhibiting HSC activation,[16,17] inhibiting the conversion of activated HSC into myo broblasts,[18] restoring the lipid droplet content in HSC,[19]. Mitochondria, which produce adenosine triphosphate (ATP), is involved in the cell signal transduction process from cell cycle, cell differentiation to apoptosis signal.[29] Mitochondria play an important role in inducing cell apoptosis by activating the pro-apoptotic protein Bcl-2 This may lead to a decrease in the mitochondrial membrane potential and the release of cytochrome c from the mitochondria into the cytoplasm, leading to initial cell apoptosis.[30] mitochondrial targeted therapy is considered as a promising strategy for the treatment of diseases.[31] The mitochondrial-mediated apoptosis pathway in hepatic broblasts is inhibited due to the overexpression of anti-apoptotic proteins (such as Bcl-2) and the blocking of mitochondrial membrane permeability.[32] Studies demonstrated that curcumin could activate the mitochondrial apoptosis pathway by regulating the level of Bcl-2 and promote the cell apoptosis.[33,34] constructing an effective delivery system to precise deliver curcumin to the mitochondria may greatly improve the clinical efficacy. The constructed delivery system was expected to improve the bioavailability of Cur in vivo and effectively treat liver brosis, thereby providing an alternative candidate for liver brosis in clinical application
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