Abstract:
:Repetitive administration is routinely used to maintain therapeutic drug levels, but previous studies have documented an accelerated blood clearance of some lipid-based delivery systems under these conditions. To assess the effect of repetitive administration, non-PEGylated lipoplexes (+/-0.5) were administered 4 times via tail vein injection at 3-day intervals to immunocompetent BALB/c mice bearing 4T1 tumors. This study measured the effect of repeat administration of nontargeted lipoplexes on clearance, cytokine/chemokine response, plasmid distribution, reporter gene expression, and liver toxicity. We do not observe a refractory period or a statistically significant difference in blood clearance between the first administration and subsequent injections of this lipoplex formulation, consistent with the absence of a cytokine/chemokine response. However, we do see a significant effect on both plasmid accumulation and expression, an enhancement of 26-fold and 10-fold in tumor plasmid levels and expression, respectively, after 4 injections as compared to that after a single injection. In addition, in vivo imaging suggests that expression in other organs had diminished rapidly 72 h after each administration, in contrast to relatively constant expression in the tumor. Taken together, the findings indicate that gene delivery to tumors can be dramatically enhanced by employing repetitive administration.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Betker JL,Anchordoquy TJdoi
10.1016/j.xphs.2016.11.013subject
Has Abstractpub_date
2017-03-01 00:00:00pages
872-881issue
3eissn
0022-3549issn
1520-6017pii
S0022-3549(16)41851-4journal_volume
106pub_type
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