期刊
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
卷 137, 期 -, 页码 218-226出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejpb.2019.03.008
关键词
PEGylation; Enfuvirtide; Lymphatic; Anti-viral; Pharmacokinetics
资金
- National Health and Medical Research Council project grant
- NHMRC Career Development fellowship
- Newton Fund RCUK-CONFAP Grant - Medical Research Council (MRC)
- Fundacao de Amparo a Pesquisa do Estado de Minas Gerais (FAPEMIG) [MR/M026302/1, APQ-00828-15]
- C.J. Martin Research Fellowship from the National Health and Medical Research Council of Australia [APP1072476]
- Jack Brockhoff Foundation [JBF 4186]
HIV therapy with anti-retroviral drugs is limited by the poor exposure of viral reservoirs, such as lymphoid tissue, to these small molecule drugs. We therefore investigated the effect of PEGylation on the anti-retroviral activity and subcutaneous lymphatic pharmacokinetics of the peptide-based fusion inhibitor enfuvirtide in thoracic lymph duct cannulated rats. Both the peptide and the PEG were quantified in plasma and lymph via ELISA. Conjugation to a single 5 kDa linear PEG decreased anti-HIV activity three-fold compared to enfuvirtide. Whilst plasma and lymphatic exposure to peptide mass was moderately increased, the loss of anti-viral activity led to an overall decrease in exposure to enfuvirtide activity. A 20 kDa 4-arm branched PEG conjugated with an average of two enfuvirtide peptides decreased peptide activity by six-fold. Plasma and lymph exposure to enfuvirtide, however, increased significantly such that anti-viral activity was increased two-and six-fold respectively. The results suggest that a multi-enfuvirtide-PEG complex may optimally enhance the anti-retroviral activity of the peptide in plasma and lymph.
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