Role of trimethylated chitosan (TMC) in nasal residence time, local distribution and toxicity of an intranasal influenza vaccine

Hagenaars, Niels; Mania, Marta; Jong, Pa de; Que, Ivo; Nieuwland, Rob; Slütter, Bram; Glansbeek, Harrie L.; Heldens, Jacco; Bosch, Han van den; Löwik, Clemens W.G.M.; Kaijzel, Eric L.; Mastrobattista, Enrico; Jiskoot, Wim

doi:10.1016/j.jconrel.2010.01.027

Cited by 58 publications

(31 citation statements)

References 34 publications

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“…[9][10][11] In contrast, N-trimethyl chitosan (TMC) is a quaternized chitosan derivative prepared by reductive methylation, which is positively charged and shows good adhesion and solubility. 12,13 Studies have used these functions to promote mucosal absorption after intranasal administration. 11,14 Lactoferrin (Lf) has a molecular weight of 80 kDa and is a naturally occurring iron-binding glycoprotein of the transferrin family.…”

Section: Introductionmentioning

confidence: 99%

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Meng¹,

Wang²,

Hua³

et al. 2018

IJN

229

101

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Background Safe and effective delivery of therapeutic drugs to the brain is important for successful therapy of Alzheimer’s disease (AD). Purpose To develop Huperzine A (HupA)-loaded, mucoadhesive and targeted polylactide-co-glycoside (PLGA) nanoparticles (NPs) with surface modification by lactoferrin (Lf)-conjugated N-trimethylated chitosan (TMC) (HupA Lf-TMC NPs) for efficient intranasal delivery of HupA to the brain for AD treatment. Methods HupA Lf-TMC NPs were prepared using the emulsion–solvent evaporation method and optimized using the Box–Behnken design. The particle size, zeta potential, drug entrapment efficiency, adhesion and in vitro release behavior were investigated. The cellular uptake was investigated by fluorescence microscopy and flow cytometry. MTT assay was used to evaluate the cytotoxicity of the NPs. In vivo imaging system was used to investigate brain targeting effect of NPs after intranasal administration. The biodistribution of Hup-A NPs after intranasal administration was determined by liquid chromatography–tandem mass spectrometry. Results Optimized HupA Lf-TMC NPs had a particle size of 153.2±13.7 nm, polydispersity index of 0.229±0.078, zeta potential of +35.6±5.2 mV, drug entrapment efficiency of 73.8%±5.7%, and sustained release in vitro over a 48 h period. Adsorption of mucin onto Lf-TMC NPs was 86.9%±1.8%, which was significantly higher than that onto PLGA NPs (32.1%±2.5%). HupA Lf-TMC NPs showed lower toxicity in the 16HBE cell line compared with HupA solution. Qualitative and quantitative cellular uptake experiments indicated that accumulation of Lf-TMC NPs was higher than nontargeted analogs in 16HBE and SH-SY5Y cells. In vivo imaging results showed that Lf-TMC NPs exhibited a higher fluorescence intensity in the brain and a longer residence time than nontargeted NPs. After intranasal administration, Lf-TMC NPs facilitated the distribution of HupA in the brain, and the values of the drug targeting index in the mouse olfactory bulb, cerebrum (with hippocampus removal), cerebellum, and hippocampus were about 2.0, 1.6, 1.9, and 1.9, respectively. Conclusion Lf-TMC NPs have good sustained-release effect, adhesion and targeting ability, and have a broad application prospect as a nasal drug delivery carrier.

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Section: Introductionmentioning

confidence: 99%

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Meng¹,

Wang²,

Hua³

et al. 2018

IJN

229

101

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“…ϩ DCs have been shown to play important roles in response to viruses (including influenza virus) (60), allergens (53), and apoptotic cells (61) and then to traffic them to the draining lymph node for presenta- …”

Section: Discussionmentioning

confidence: 99%

CpG Oligodeoxynucleotides Facilitate Delivery of Whole Inactivated H9N2 Influenza Virus via Transepithelial Dendrites of Dendritic Cells in Nasal Mucosa

Qin

Yin

et al. 2015

J Virol

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The spread of the low-pathogenicity avian H9N2 influenza virus has seriously increased the risk of a new influenza pandemic. Although whole inactivated virus (WIV) vaccine via intranasal pathway is the effective method of blocking virus transmission, the mucosal barrier seems to be a major factor hampering its development. CpG oligodeoxynucleotides, a known adjuvant, can target downstream dendritic cells (DCs) and effectively enhance the mucosal and systemic immune responses. However, the ability of CpGs to assist H9N2 WIV in transepithelial transport remains unknown. Here, in vitro and in vivo, we showed that CpGs provided assistance for H9N2 WIV in recruiting DCs to the nasal epithelial cells (ECs) and forming transepithelial dendrites (TEDs) to capture luminal viruses. CD103؉ DCs participated in this process. Chemokine CCL20 from nasal ECs played a key role in driving DC recruitment and TED formation. Virus-loaded DCs quickly migrated into the draining cervical lymph nodes (CLNs) for antigen presentation. In addition, the competence of CpGs was independent of direct epithelial transport via the transcellular or paracellular pathway. Taken together, our data demonstrated that CpGs enhanced the transport of H9N2 WIV via TEDs of nasal DCs, which might be a novel mechanism for optimal adaptive immune responses. IMPORTANCE This paper demonstrates by both an in vivo and an in vitro coculture model that CpG oligodeoxynucleotides, known as an adjuvant generally targeting downstream immune responses, also are crucial for the transport of H9N2 WIV across nasal epithelial cells (ECs) via the uptake of transepithelial dendrites (TEDs).Our results prove for the first time to our knowledge that the immune-potentiating mechanism of CpGs is based on strengthening the transepithelial uptake of H9N2 WIV in nasal mucosa. These findings provide a fresh perspective for further improvement of intranasal influenza vaccines, which are urgently needed in the face of the potential threat of H9N2 influenza.T he prevention and control of influenza are becoming more and more urgent, especially given the recent avian influenza A (H7N9) outbreaks in China (1). This subtype is primarily reassorted with enzootic H9N2 viruses that have circulated widely among birds in the Far East and the Middle East since the late 1990s (2). Based on their safety profile, high immunogenicity, and the capability of establishing cross-protection at the pathogen's entry site and interrupting viral transmission (3-6), whole inactivated H9N2 influenza vaccines given via intranasal (i.n.) immunization are very effective for virus elimination. Nonetheless, the efficacy of intranasal immunization is currently poor, primarily because of the physiology of the nasal cavity. Antigens have to find their way to overcome a series of barriers (mucus, cilia, and compact epithelium) before they are absorbed into the body (7). Numerous studies have attempted to improve the effect of i.n. whole inactivated virus (WIV) influenza vaccines by using mucoadhesive particulate...

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“…N, N, N-trimethyl chitosan chloride (TMC), as a representative of quaternized chitosan derivatives, showed a variety of improved biological properties, such as increased solubility, enhanced mucosa adhesiveness and permeation ability (Benediktsdottir et al 2013;Hagenaars et al 2010). The degree of quaternization (DQ) can affect both solubility and mucoadhesion of TMC.…”

Section: Structure Modification Of Chitosanmentioning

confidence: 99%

Drug Delivery Applications of Chitosan and its Derivatives

Zhang

Mao

2015

Excipient Applications in Formulation Design and Drug Delivery

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The development of drug delivery systems always goes hand in hand with the advancement of material science. The novel synthetic or natural functional materials provide opportunities to design optimal drug delivery systems. Among these, chitosan and its derivatives exhibit excellent application future because of its prominent characteristics. In this chapter, research progress of chitosan and its derivatives for drug delivery, from structure to properties, from properties to its application were overviewed. The physicochemical properties, biological properties, biodegradability, safety evaluation and structure modification of chitosan were introduced. Furthermore, applications of chitosan and its derivatives in drug delivery including as the carrier of nanoparticles and microparticles, as coating material, as matrix of hydrogels, films and sustained release tablets, as stabilizers, as absorption enhancers, were discussed. Finally, the applications of chitosan and its derivatives in different administration routes, and their advantages for gene, protein and vaccine delivery, were reviewed. The numerous successful studies on exploitation and application of chitosan and its derivatives showed promising application future of these materials in drug delivery.

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Role of trimethylated chitosan (TMC) in nasal residence time, local distribution and toxicity of an intranasal influenza vaccine

Cited by 58 publications

References 34 publications

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

CpG Oligodeoxynucleotides Facilitate Delivery of Whole Inactivated H9N2 Influenza Virus via Transepithelial Dendrites of Dendritic Cells in Nasal Mucosa

Drug Delivery Applications of Chitosan and its Derivatives

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Role of trimethylated chitosan (TMC) in nasal residence time, local distribution and toxicity of an intranasal influenza vaccine

Cited by 58 publications

References 34 publications

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer&rsquo;s disease

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer&rsquo;s disease

CpG Oligodeoxynucleotides Facilitate Delivery of Whole Inactivated H9N2 Influenza Virus via Transepithelial Dendrites of Dendritic Cells in Nasal Mucosa

Drug Delivery Applications of Chitosan and its Derivatives

Contact Info

Product

Resources

About

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease

Intranasal delivery of Huperzine A to the brain using lactoferrin-conjugated N-trimethylated chitosan surface-modified PLGA nanoparticles for treatment of Alzheimer’s disease