fabrication-dissolvable-microneedle-patches-loaded-with-lactalbumin

Fabrication of Dissolvable Microneedle Patches Loaded with &#945;-Lactalbumin Nanomicelles for Transdermal Capsaicin Delivery and Adipose Tissue Reduction

This protocol outlines the fabrication and application of dissolvable microneedle (MN) patches containing &#945;-lactalbumin nanomicelles for the targeted ...

Ludong University

Mucus is a viscoelastic biological hydrogel that protects the epithelial surface from penetration by most nanoparticles, which limits the efficiency of oral drug delivery. Pursuing highly efficient, biocompatible, and biodegradable oral drug vehicles is of central importance to the development of promising nanomedicine. Here, we prepared five peptosomes (PSs) with various sizes, shapes, and rigidities based on self-assembly of amphiphilic α-lactalbumin (α-lac) peptides from partial enzymolysis and cross-linking. The mucus permeation of α-lac PSs and release of curcumin (Cur) encapsulated in these PSs were evaluated. Compared with a long nanotube, big nanosphere, small nanosphere, and cross-linked short nanotube, we demonstrated that a short nanotube (SNT) exhibits excellent permeability in mucus, which enables it to arrive at epithelial cells quickly. Besides, SNT exhibits the highest cellular uptake and transmembrane permeability on Caco-2/HT29-MTX (E12) 3D coculture model. In vivo pharmacokinetic evaluation revealed that SNT formulation shows the highest curcumin bioavailability, which is 6.85-folds higher than free Cur. Most importantly, Cur loaded in SNT exhibits the optimum therapeutic efficacy for in vivo treatment of dextran sulfate sodium (DSS)-induced ulcerative colitis. In the end, the mechanism of the high permeability of SNTs through mucus was explained by coarse-grained molecular dynamics simulations, which indicated that short time scale jiggling and flying across pores of mucus network played key roles. These findings revealed the tubular α-lac PSs could be a promising oral drug delivery system targeted to mucosal for improving absorption and bioavailability of hydrophobic bioactive ingredients.

Enhanced Transport of Shape and Rigidity-Tuned α-Lactalbumin Nanotubes across Intestinal Mucus and Cellular Barriers.

Inflammatory cytokine tumor necrosis factor-α (TNFα) has been demonstrated to accelerate the progression and metastasis of various carcinomas. In this study, we investigated the effect of amentoflavone on inhibiting the migration and invasion of TNFα-induced breast cancer cells. Results showed that amentoflavone significantly blocked the cellular migration and invasion of MCF10DCIS.com and MDA-MB-231 cells at a concentration of 10 μM but did not affect the cell viability. The mRNA and protein levels of matrix metalloproteinase (MMP)-9, significantly activated by TNFα, were reversed by amentoflavone treatment in a dose-dependent manner in MCF10DCIS.com cells. Congruent with the protein level, the activity of MMP-9 was significantly suppressed by amentoflavone treatment. Additionally, we found that amentoflavone dampened Gli1-dependent noncanonical hedgehog signaling, which is a key factor in the regulation of migration and invasion in TNFα-induced human breast cancer cells. Further study elucidated that TNFα enhanced Gli1 through the activation of the AKT/mTOR/S6K1 cascade, whereas it receded after amentoflavone treatment in human breast cancer cells. In summary, amentoflavone abrogated Gli1 activation in TNFα-induced mammary tumor cells, resulting in a decrease of invasiveness in human breast cancer cells  mediating AKT/mTOR/S6K1 signaling. Amentoflavone should be considered as a potent food ingredient for the retardation of mammary tumorigenesis.

Amentoflavone inhibits tumor necrosis factor-α-induced migration and invasion through AKT/mTOR/S6k1/hedgehog signaling in human breast cancer.

Sustained oral uncoupler 2,4-dinitrophenol (DNP) administration exerts prominent anti-obesity effects, but the adipose tissue off-target disadvantage leads to systemic adverse effects. A novel non-cardiotoxicity DNP delivery method using a biocompatible microneedles patch containing the amphiphilic tetradecanoic acid-DNP ester (TADNP) is described, which is synthesized via esterification on the phenolic hydroxyl of DNP. The TADNP is self-assembled as nanomicelles, which enhance the endocytosis rate of DNP by adipocytes and its permeation in isolated adipose tissues. The microenvironment of adipose tissues promotes the massive release of DNP and plasma and simulated gastrointestinal fluids. The microneedles-delivered TADNP nanomicelles (MN-TADNP) effectively deliver DNP in treated adipose tissues and reduce DNP content in off-target organs. Both oral and MN patch-delivered TADNP micelles effectively exert anti-obesity effects in a mouse model of high-fat diet-induced obesity; and noteworthily, MN-TADNP exhibit more satisfactory biosafety than oral administration. Here, a smart MN patch loaded with tetradecanoic acid-modified DNP is reported, which enhances its accumulation in adipose tissues and exerts an anti-obesity effect without causing any systemic toxicity.

Non-Cardiotoxic Tetradecanoic Acid-2,4-Dinitrophenol Ester Nanomicelles in Microneedles Exert Potent Anti-Obesity Effect by Regulating Adipocyte Browning and Lipogenesis.

Rutin, a flavonoid glycoside phytochemical compound, has a remarkable antiobesity effect. However, its therapeutic potential is hindered by its poor water solubility and low oral bioavailability. In this study, rutin was loaded into liposomes (LR) through the self-assembly of lecithin and cholesterol. It was discovered that liposomes improved the water solubility and cellular uptake of rutin in adipocytes. These rutin-loaded liposomes were then incorporated into a microneedle patch (MP) system formed by polyvinylpyrrolidone and poly(vinyl alcohol), and the MP-LR showed an increased release percentage in the adipose tissue microenvironment of pH 6.5 and achieved local delivery of rutin into adipocytes. Next, the therapeutic potentials of rutin, LR, and MP-LR were investigated in a high-fat diet (HFD)-induced obese mouse model. The MP-LR formulation decreased the weight of the HFD mice the most significantly. The antilipogenesis mechanisms of MP-LR are downregulating the lipid synthesis-related proteins (PPAR γ and C/EBP α) in adipocytes and promoting the expression of the beige adipogenesis-related proteins (UCP 1 and Cyt C). The MP systems further promote the local penetration of LR into the adipose tissue specifically, which again elevates their antiobesity effect. Overall, this study suggests that MP-delivered liposome-based formulation is a promising approach to enhance the antiobesity efficacy of antilipogenesis bioactive compounds.

Article	Year
Enhanced Transport of Shape and Rigidity-Tuned α-Lactalbumin Nanotubes across Intestinal Mucus and Cellular Barriers. Nano letters\| PubMed ID: 31904988	2020
Amentoflavone inhibits tumor necrosis factor-α-induced migration and invasion through AKT/mTOR/S6k1/hedgehog signaling in human breast cancer. Food & function\| PubMed ID: 34542136	2021
Non-Cardiotoxic Tetradecanoic Acid-2,4-Dinitrophenol Ester Nanomicelles in Microneedles Exert Potent Anti-Obesity Effect by Regulating Adipocyte Browning and Lipogenesis. Small (Weinheim an der Bergstrasse, Germany)\| PubMed ID: 37259675	2023
Antilipogenesis Effect of Rutin-Loaded Liposomes Using a Microneedle Delivery System. ACS applied materials & interfaces\| PubMed ID: 37972277	2023

Cheng Bao

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