Effects of intravenous and subcutaneous administration on the pharmacokinetics, biodistribution, cellular uptake and immunostimulatory activity of CpG ODN encapsulated in liposomal nanoparticles

Despite more than two decades of research and development on nucleic acid vaccines, there is still no commercial product for human use. Taking advantage of the recent innovations in systemic delivery of short interfering RNA (siRNA) using lipid nanoparticles (LNPs), we developed a self-amplifying RNA vaccine. Here we show that nonviral delivery of a 9-kb self-amplifying RNA encapsulated within an LNP substantially increased immunogenicity compared with delivery of unformulated RNA. This unique vaccine technology was found to elicit broad, potent, and protective immune responses, that were comparable to a viral delivery technology, but without the inherent limitations of viral vectors. Given the many positive attributes of nucleic acid vaccines, our results suggest that a comprehensive evaluation of nonviral technologies to deliver self-amplifying RNA vaccines is warranted.vaccine platform | SAM vaccine | respiratory syncytial virus | HIV

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“…LNP delivery systems with low surface charge are sequestered by antigen presenting cells after s.c. administration (35,36). For .…”

Section: Discussionmentioning

confidence: 99%

Nonviral delivery of self-amplifying RNA vaccines

Geall

Verma

Otten

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

568

528

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“…Thus, their uptake into the lymphatics is limited. [22,25] As most chemotherapeutics for the treatment of melanoma are small molecules without the necessary properties for lymphatic uptake, a drug delivery system is needed to achieve the necessary lymphatic accumulation.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni

Kyryachenko

Chagani

et al. 2015

Journal of Controlled Release

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Metastatic Melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NP) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NP are similarly sized (~ 48nm), with neutral, partially charged, or fully charged surface. The NP are able to load ~ 2mg/mL of each drug and are stable for 24 h. The NP are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NP were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NP are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NP are efficacious at the proximal LN, while the fully charged NP have no effect on either LN. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NP have the highest potential in treating metastatic melanoma. GRAPHICAL ABSTRACT

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“…Общее количество ДНК, размер фрагментов и время её циркуляции в крови определяются активностью нуклеаз крови [39,45], структурой ДНК (наличием/отсутствием метилированных цитозинов) [46], формой цирДНК (свободная или в составе комплексов) [47], а также наличием биополимеров [48][49], которые могут связываться с нуклеиновыми кислотами, защищая их от нуклеазной атаки или, напротив, дестабилизируя нуклеопротеиновые компоненты. Эти аспекты циркуляции ДНК в кровотоке будут более детально рассмотрены ниже.…”

Section: состав циркулирующих в крови комплексов внеклеточных днкunclassified

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

Bryzgunova

Laktionov

2015

BIOMED KHIM

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Внеклеточные нуклеиновые кислоты (внНК) в циркуляции как здоровых, так и больных людей были впервые описаны в 1948 г., однако оставались без внимания до середины 60-х годов прошлого века. внНК особенно интенсивно исследуются в последние 5 лет. Основное внимание уделяется исследованию внНК как источнику диагностического материала; однако механизмы генерации внеклеточных нуклеиновых кислот, а также механизмы, обеспечивающие их долговременную циркуляцию в кровотоке, однозначно не установлены. По данным одних авторов, основным источником циркулирующих дезоксирибонуклеиновых кислот в крови (цирДНК) являются процессы некроза и апоптоза, другие ссылаются на возможную секрецию нуклеиновых кислот как здоровыми, так и опухолевыми клетками. Известно, что цирДНК могут циркулировать в крови в течение длительного времени, ускользая от действия ДНК-гидролизующих ферментов крови и, по-видимому, находясь в составе надмолекулярных комплексов. В этом обзоре представлены данные разных авторов и приведены доказательства в пользу всех предложенных теорий появления цирДНК, описаны особенности строения цирДНК, а также факторы, влияющие на время циркуляции ДНК в крови.Ключевые слова: циркулирующая ДНК, апоптоз, некроз, активная секреция, ДНКазы, метилирование.

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Effects of intravenous and subcutaneous administration on the pharmacokinetics, biodistribution, cellular uptake and immunostimulatory activity of CpG ODN encapsulated in liposomal nanoparticles

Cited by 65 publications

References 38 publications

Nonviral delivery of self-amplifying RNA vaccines

Nonviral delivery of self-amplifying RNA vaccines

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Generation of blood circulating DNA: the sources, peculiarities of circulation and structure

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