Liposome associated interferon-alpha-2b functions as an anti-fibrogenic factor in dermal wounds in the guinea pig.
We have previously reported that interferon-alpha-2b (IFN-alpha-2b) can be encapsulated in liposomes without compromising its anti-fibrogenic effects on dermal fibroblasts in vitro. This study was conducted to determine whether this preparation applied topically to guinea pig wounds can affect their healing. The rationale for this approach is that systemic administration of IFN-alpha-2b by injection for treatment of dermal fibrosis is uncomfortable, requires a large quantity of the cytokine and cannot be easily used in children. Liposomes are potentially useful vehicles for the topical delivery of drugs. Empty sonicated liposome vesicles were mixed with various concentrations of IFN-alpha-2b and then dried and rehydrated. An enzyme-linked immunosorbent assay (ELISA) was used to determine the efficiency of encapsulation and the stability of the preparation under experimental conditions. A total of 36 full thickness skin wounds (6/animal, 3 on each side) were made with an 8 mm disposable punch. Each wound on the right side received cream (100 mg/wound) containing 3000 units of liposome-encapsulated IFN-alpha-2b, while wounds on the left side received cream containing empty liposomes. There was a significant reduction in rate of contraction of wounds treated with IFN-alpha-2b as early as 5 days after wounding. This reduction remained significant up to 10 days. Northern analysis, used to evaluate the expression of mRNAs for type I and type III collagens in response to IFN-alpha-2b showed a marked reduction in abundance of the transcripts for the pro-alpha1(I) chain of type 1 collagen on days 11 and 14 after wounding. Similarly, the level of mRNA for type III procollagen was markedly reduced as early as day 7 and remained depressed up to day 14. These findings were consistent with results obtained for the total collagen content in tissue samples. Cellularity of the IFN-alpha-2b-treated wounds, assessed by vimentin content, was also markedly reduced at day 7 and remained depressed up to day 14. Liposome associated IFN-alpha-2b applied 5 days after completion of epithelialization reduced mRNA for the pro-alpha1(I) chain of type 1 collagen, confirming its transepidermal penetration and effectiveness. The activity of liposome-associated IFN-alpha-2b in vivo supports the concept of the topical use of this anti-fibrogenic agent for treatment of fibroproliferative disorders.
Ghahary
A
A
Department of Surgery, University of Alberta, Edmonton, Canada.
Tredget
E E
EE
Shen
Q
Q
Kilani
R T
RT
Scott
P G
PG
Takeuchi
M
M
D000279:Administration, Cutaneous; D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000293:injuries* / Q000473:pathology*; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis; D006168:Guinea Pigs; D006909:Hydroxyproline / Q000032:analysis; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000494:pharmacology; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D014746:Vimentin / Q000032:analysis; D014945:Wound Healing / Q000187:drug effects*
D004337:Drug Carriers; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008081:Liposomes; D011498:Protein Precursors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014746:Vimentin; D003094:Collagen; D006909:Hydroxyproline