PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases.
Title | PEGylation of interferon α2 improves lymphatic exposure after subcutaneous and intravenous administration and improves antitumour efficacy against lymphatic breast cancer metastases. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Kaminskas LM, Ascher DB, McLeod VM, Herold MJ, Le CP, Sloan EK, Porter CJH |
Journal | J Control Release |
Volume | 168 |
Issue | 2 |
Pagination | 200-8 |
Date Published | 2013 Jun 10 |
ISSN | 1873-4995 |
Keywords | Administration, Intravenous, Animals, Antineoplastic Agents, Breast Neoplasms, Female, Humans, Injections, Subcutaneous, Interferon-alpha, Lymph, Lymphatic Metastasis, Male, Mice, Mice, Nude, Polyethylene Glycols, Rats, Rats, Sprague-Dawley, Recombinant Proteins, Treatment Outcome |
Abstract | The efficacy of protein-based therapeutics with indications in the treatment of lymphatic diseases is expected to be improved by enhancing lymphatic disposition. This study was therefore aimed at examining whether PEGylation can usefully be applied to improve the lymphatic uptake of interferon α2 and whether this ultimately translates into improved therapeutic efficacy against lymph-resident cancer. The lymphatic pharmacokinetics of interferon α2b (IFN, 19kDa) and PEGylated interferon α2b (IFN-PEG12, 31kDa) or α2a (IFN-PEG40, 60kDa) was examined in thoracic lymph duct cannulated rats. IFN was poorly absorbed from the SC injection site (Fabs 36%) and showed little uptake into lymph after SC or IV administration (≤1%). In contrast, IFN-PEG12 was efficiently absorbed from the SC injection site (Fabs 82%) and approximately 20% and 8% of the injected dose was recovered in thoracic lymph over 30h after SC or IV administration respectively. IFN-PEG40, however, was incompletely absorbed from the SC injection site (Fabs 23%) and showed similar lymphatic access after SC administration to IFN-PEG12 (21%). The recovery of IFN-PEG40 in thoracic lymph after IV administration, however, was significantly greater (29%) when compared to IV IFN-PEG12. The anti-tumour efficacy of interferon against axillary metastases of a highly lymph-metastatic variant of human breast MDA-MB-231 carcinoma was significantly increased by SC administration of lymph-targeted IFN-PEG12 when compared to the administration of IFN on the ipsilateral side to the axillary metastasis. Optimal PEGylation may therefore represent a viable approach to improving the lymphatic disposition and efficacy of therapeutic proteins against lymphatic diseases. |
DOI | 10.1016/j.jconrel.2013.03.006 |
Alternate Journal | J Control Release |
PubMed ID | 23499718 |
PubMed Central ID | PMC4022972 |
Grant List | CA160890 / CA / NCI NIH HHS / United States R01 CA160890 / CA / NCI NIH HHS / United States |