“… 19 PMs could enhance the oral bioavailability and antitumor efficacy of poorly soluble drugs. 51 , 52 Hence, TPGS polymeric micelles could improve the inhibitory effect of HF against breast cancer, although this needs to be confirmed in a follow-up pharmacokinetics study. Figure 5 Anticancer effect of HTPM orally administrated against subcutaneous TNBC xenografts in nude mice.…”
Background
Halofuginone (HF)-loaded TPGS polymeric micelles (HTPM) were successfully fabricated using the thin-film hydration technique. HTPM via intravenous injection have been demonstrated to exert an excellent anticancer effect against triple-negative breast cancer (TNBC) cells and subcutaneous xenografts. In the present study, we further explored the potential treatment effect and mechanism of orally administered HTPM alone and in combination with surgical therapy on TNBC in subcutaneous and orthotopic mouse models.
Methods
Herein, the stability and in vitro release behavior of HTPM were first evaluated in the simulated gastrointestinal fluids. Caco-2 cell monolayers were then used to investigate the absorption and transport patterns of HF with/without encapsulation in TPGS polymeric micelles. Subsequently, the therapeutic effect of orally administered HTPM was checked on subcutaneous xenografts of TNBC in nude mice. Ultimately, orally administered HTPM, combined with surgical therapy, were utilized to treat orthotopic TNBC in nude mice.
Results
Our data confirmed that HTPM exhibited good stability and sustained release in the simulated gastrointestinal fluids. HF was authenticated to be a substrate of P-glycoprotein (P-gp), and its permeability across Caco-2 cell monolayers was markedly enhanced via heightening intracellular absorption and inhibiting P-gp efflux due to encapsulation in TPGS polymeric micelles. Compared with HF alone, HTPM showed stronger tumor-suppressing effects in subcutaneous xenografts of MDA-MB-231 cells when orally administered. Moreover, compared with HTPM or surgical therapy alone, peroral HTPM combined with partial surgical excision synergistically retarded the growth of orthotopic TNBC. Fundamentally, HTPM orally administered at the therapeutic dose did not cause any pathological injury, while HF alone led to weight loss and jejunal bleeding in the investigated mice.
Conclusion
Taken together, HTPM could be applied as a potential anticancer agent for TNBC by oral administration.
“… 19 PMs could enhance the oral bioavailability and antitumor efficacy of poorly soluble drugs. 51 , 52 Hence, TPGS polymeric micelles could improve the inhibitory effect of HF against breast cancer, although this needs to be confirmed in a follow-up pharmacokinetics study. Figure 5 Anticancer effect of HTPM orally administrated against subcutaneous TNBC xenografts in nude mice.…”
Background
Halofuginone (HF)-loaded TPGS polymeric micelles (HTPM) were successfully fabricated using the thin-film hydration technique. HTPM via intravenous injection have been demonstrated to exert an excellent anticancer effect against triple-negative breast cancer (TNBC) cells and subcutaneous xenografts. In the present study, we further explored the potential treatment effect and mechanism of orally administered HTPM alone and in combination with surgical therapy on TNBC in subcutaneous and orthotopic mouse models.
Methods
Herein, the stability and in vitro release behavior of HTPM were first evaluated in the simulated gastrointestinal fluids. Caco-2 cell monolayers were then used to investigate the absorption and transport patterns of HF with/without encapsulation in TPGS polymeric micelles. Subsequently, the therapeutic effect of orally administered HTPM was checked on subcutaneous xenografts of TNBC in nude mice. Ultimately, orally administered HTPM, combined with surgical therapy, were utilized to treat orthotopic TNBC in nude mice.
Results
Our data confirmed that HTPM exhibited good stability and sustained release in the simulated gastrointestinal fluids. HF was authenticated to be a substrate of P-glycoprotein (P-gp), and its permeability across Caco-2 cell monolayers was markedly enhanced via heightening intracellular absorption and inhibiting P-gp efflux due to encapsulation in TPGS polymeric micelles. Compared with HF alone, HTPM showed stronger tumor-suppressing effects in subcutaneous xenografts of MDA-MB-231 cells when orally administered. Moreover, compared with HTPM or surgical therapy alone, peroral HTPM combined with partial surgical excision synergistically retarded the growth of orthotopic TNBC. Fundamentally, HTPM orally administered at the therapeutic dose did not cause any pathological injury, while HF alone led to weight loss and jejunal bleeding in the investigated mice.
Conclusion
Taken together, HTPM could be applied as a potential anticancer agent for TNBC by oral administration.
“…The low rate of Cur permeation may be due to viscous nature of aqueous humour that hinders the permeation and causes the retention of Cur in mucus. As the purpose of this study was to ensure the penetration of PEG-CUR-C6 ointment in aqueous humour so we can also use this ointment to target posterior segment of eye to treat ophthalmic diseases [ 27 ].…”
Naturally occurring curcumin can be used for the treatment of corneal bacterial infections with its limitation of poor solubility. Aim of the present study was to enhance solubility and permeation of curcumin for the treatment of corneal bacterial infections. For increasing solubility, curcumin and polyethylene glycol (PEG 6000) complex (1:3) was prepared by fusion melting method. Phase solubility studies were used for the calculation of Gibbs free energy of curcumin. Central composite rotatable design (CCRD) was applied for optimization of Curcumin (CUR), PEGylated Curcumin (PEG-CUR), penetration enhancer cremophore (CR). Optimized ointments were further evaluated by mucous permeation, membrane permeability and cell toxicity studies by Transwell cell, ussing chamber and Caco-2 cells respectively. Antibacterial test was also performed by agar well diffusion method. Solubility of PEG-CUR was increased up to 93±3.2% as compared to pure curcumin and content uniformity was in the range of 95â110%. Curcumin permeation from PEG-CUR ointment was increased up to 12 folds. No toxicity of Caco-2 cells for PEG-CUR even after 24h was observed. Activity index of pure CUR, PEG-CUR ointment with or without CR against S. aureus and P. aeruginosa was 97±2.3, 96±1.6, 95±2.5% respectively. Ointment with solubility enhanced PEG-CUR and cremophore can be used as a promising tool for the treatment of corneal bacterial infections.
“…This can also be seen by the variability in the plasma concentrations in animal models in terms of the oral administration of non-formulated and formulated curcumin provided in Table 4. [143] Galactosamine-modified PEG-PLGA micelles / 5.0 [117] Solutol HS15 +TPGS, Solutol HS15+Pluronic 127 mixed micelles 6.0 46 (for more successful TPGS-based formulation) [127] So far, only a handful of pharmacokinetics studies on different formulation approaches for oral delivery of natural Nrf2 modulators have been carried out in humans. In particular, the evaluation of the clinical translatability of nanoDDSs (e.g., nanocrystals, polymeric nanoparticles, SLNs, micelles) is falling far behind the broad selection of preclinical pharmacokinetics studies that have been carried out.…”
Section: Discussionmentioning
confidence: 99%
“…Carrier-based nanoDDSs have also been frequently studied for the improvement of the solubility and oral bioavailability of natural Nrf2 modulators. These have included nan-oDDSs such as polymeric nanoparticles [115], solid lipid nanoparticles [116], micelles [117], nanoemulsions [118], liposomes [119,120], and dendrimers [121]. The improvement of the Nrf2 modulator oral bioavailability by encapsulation in nanoDDSs is based on the follow-ing mechanisms: (i) protection of the drug from enzymatic degradation in the GI tract (e.g., curcumin, which shows such instability); (ii) increased solubility and dissolution rate of the drug; (iii) adhesion-mediated increased gastric or intestinal residence time; and (iv) absorption of the entire nanocarriers.…”
Oxidative stress is associated with a wide range of diseases characterised by oxidant-mediated disturbances of various signalling pathways and cellular damage. The only effective strategy for the prevention of cellular damage is to limit the production of oxidants and support their efficient removal. The implication of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in the cellular redox status has spurred new interest in the use of its natural modulators (e.g., curcumin, resveratrol). Unfortunately, most natural Nrf2 modulators are poorly soluble and show extensive pre-systemic metabolism, low oral bioavailability, and rapid elimination, which necessitates formulation strategies to circumvent these limitations. This paper provides a brief introduction on the cellular and molecular mechanisms involved in Nrf2 modulation and an overview of commonly studied formulations for the improvement of oral bioavailability and in vivo pharmacokinetics of Nrf2 modulators. Some formulations that have also been studied in vivo are discussed, including solid dispersions, self-microemulsifying drug delivery systems, and nanotechnology approaches, such as polymeric and solid lipid nanoparticles, nanocrystals, and micelles. Lastly, brief considerations of nano drug delivery systems for the delivery of Nrf2 modulators to the brain, are provided. The literature reviewed shows that the formulations discussed can provide various improvements to the bioavailability and pharmacokinetics of natural Nrf2 modulators. This has been demonstrated in animal models and clinical studies, thereby increasing the potential for the translation of natural Nrf2 modulators into clinical practice.
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