Establishment and validation of an ex vivo human cervical tissue model for local delivery studies.
The objective of this study was to establish and validate an ex vivo human cervical tissue model appropriate for transport studies of molecular and especially nucleic acid based drugs. For that purpose conditions had to be established for a standardized tissue handling and preparation following hysterectomy to allow an immediate experimental use of fresh tissue samples. Samples of the ectocervical, endocervical and the transition zone representing the entire cervix organ were characterized in Franz diffusion cells by the determination of the in vitro permeation of low and high molecular weight markers (propanolol, mannitol, dextran 4000, 10,000, 20,000 and 40,000Da). Additionally, the permeability of mannitol and dextran 4000 across fresh and frozen cervical tissue was compared. The apparent permeability coefficients (P(app)) of the various markers demonstrated (i) that with increasing molecular weight the marker permeability decreases, (ii) an upper permeability limit between 10,000 and 20,000Da, (iii) no significant difference of the permeability across the three cervical tissue zones, (iv) a statistically significant but effectively small variation of the permeability among different patient samples. A continuous difference of approximately two log values between the P(app) values of mannitol and dextran 4000 makes them suitable as an internal marker control pair for each biopsy. Moreover, the P(app) values of both markers across fresh and frozen tissue are comparable. According to the presented data we conclude that the human cervical tissue model has been well characterized and is therefore suitable for local delivery and permeation studies.
Hexal Gentech ForschungsGmbH, Holzkirchen, Germany.
Christian
C
Hiller
Udo
U
Bock
Sigrid
S
Balser
Eleonore
E
Haltner-Ukomadu
Michael
M
Dahm
D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D009696:Nucleic Acids / Q000737:chemistry / Q000493:pharmacokinetics*; D010539:Permeability; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology*
D009696:Nucleic Acids