Protein stabilization by cyclodextrins in the liquid and dried state

“…Natural cyclodextrins contain six (a-CD), seven (b-CD), eight (g-CD), or more (a-1,4)-linked a-d-glucopyranose units, and many chemically modified cyclodextrins have been developed, including hydroxypropyl-b-cyclodextrin (HP-b-CD) and sulfobutyl etherb-cyclodextrin (9). Because of their molecular structure and shape, the cyclodextrins can form an inclusion complex with hydrophobic molecules, improving the solubility of hydrophobic drugs (9), stabilizing proteins (10), and controlling the release of drugs (11). For these reasons, cyclodextrins are widely used excipients for pharmaceutical agents (9).…”

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confidence: 99%

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

Onishi

Ozasa

Kobiyama

et al. 2015

The Journal of Immunology

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Cyclodextrins are commonly used as a safe excipient to enhance the solubility and bioavailability of hydrophobic pharmaceutical agents. Their efficacies and mechanisms as drug-delivery systems have been investigated for decades, but their immunological properties have not been examined. In this study, we reprofiled hydroxypropyl-β-cyclodextrin (HP-β-CD) as a vaccine adjuvant and found that it acts as a potent and unique adjuvant. HP-β-CD triggered the innate immune response at the injection site, was trapped by MARCO+ macrophages, increased Ag uptake by dendritic cells, and facilitated the generation of T follicular helper cells in the draining lymph nodes. It significantly enhanced Ag-specific Th2 and IgG Ab responses as potently as did the conventional adjuvant, aluminum salt (alum), whereas its ability to induce Ag-specific IgE was less than that of alum. At the injection site, HP-β-CD induced the temporary release of host dsDNA, a damage-associated molecular pattern. DNase-treated mice, MyD88-deficient mice, and TBK1-deficient mice showed significantly reduced Ab responses after immunization with this adjuvant. Finally, we demonstrated that HP-β-CD–adjuvanted influenza hemagglutinin split vaccine protected against a lethal challenge with a clinically isolated pandemic H1N1 influenza virus, and the adjuvant effect of HP-β-CD was demonstrated in cynomolgus macaques. Our results suggest that HP-β-CD acts as a potent MyD88- and TBK1-dependent T follicular helper cell adjuvant and is readily applicable to various vaccines.

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“…In particular, the poloxamer 407 (P407; Pluronic® F127, BASF, Germany), a thermo-reversible copolymer with an amphiphilic nature consisting of a central hydrophobic block of polypropylene oxide (PPO) flanked by hydrophilic polyethylene blocks (PEG-PPO-PEG), has held interest in the design of dermal, subcutaneous, and transdermal delivery systems, aiming to improve drug permeation and liberation through the skin (Akash and Rehman 2015). Poloxamers have been applied for a very broad range in biomedical and pharmaceutical industries, as well as for agriculture, paper and coatings, photography, personal care, and detergents Serno et al 2011). Moreover, these products are easily manufactured and have efficient targeting ability (Torchilin et al 2001).…”

Section: Discussionmentioning

confidence: 99%

An 8-hydroxyquinoline-containing polymeric micelle system is effective for the treatment of murine tegumentary leishmaniasis

et al. 2016

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The current treatment of leishmaniasis has been hampered due to the high toxicity of the available drugs and long duration protocols, which often lead to its abandonment. In the present study, a poloxamer 407-based delivery system was developed, and a molecule, 8-hydroxyquinoline (8-HQN), was incorporated with it, leading to an 8-HQN/micelle (8-HQN/M) composition. Assays were performed to evaluate the in vitro antileishmanial activity of 8-HQN/M against Leishmania amazonensis stationary promastigotes. The cytotoxicity in murine macrophages and in human red cells, as well as the efficacy of the treatment in macrophages infected by parasites, was also assessed. This product was also evaluated for the treatment of murine tegumentary leishmaniasis, using L. amazonensis-infected BALB/c mice. To evaluate the in vivo efficacy of the treatment, the average lesion diameter (area) in the infected tissue, as well as the parasite load at the site of infection (skin), spleen, liver and draining lymph nodes were examined. Non-incorporated micelle (B-8-HQN/M) and the free molecule (8-HQN) were used as controls, besides animals that received only saline. The parasite burden was evaluated by limiting dilution and quantitative real-time PCR (qPCR) techniques, and immunological parameters associated with the treatments were also investigated. In the results, the 8-HQN/M group, when compared to the others, presented more significant reductions in the average lesion diameter and in the parasite burden in the skin and all evaluated organs. These animals also showed significantly higher levels of parasite-specific IFN-γ, IL-12, and GM-CSF, associated with low levels of IL-4 and IL-10, when compared to the saline, 8-HQN/M, and B-8-HQN groups. A predominant IL-12-driven IFN-γ production, against parasite proteins, mainly produced by CD4 T cells, was observed in the treated animals, post-infection. In conclusion, 8-HQN/M was highly effective in treating L. amazonensis-infected BALB/c mice and can be considered alone, or combined with other drugs, as an alternative treatment for tegumentary leishmaniasis. Graphical Abstract Therapeutic scheme and immunological and parasitological parameters developed in the present study.

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Protein stabilization by cyclodextrins in the liquid and dried state

Cited by 154 publications

References 169 publications

Mammalian cell-produced therapeutic proteins: heterogeneity derived from protein degradation

Mammalian cell-produced therapeutic proteins: heterogeneity derived from protein degradation

Hydroxypropyl-β-Cyclodextrin Spikes Local Inflammation That Induces Th2 Cell and T Follicular Helper Cell Responses to the Coadministered Antigen

An 8-hydroxyquinoline-containing polymeric micelle system is effective for the treatment of murine tegumentary leishmaniasis

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