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Tissue Permeability Effects Associated with the Use of Mucoadhesive Cationic Nanoformulations of Docetaxel in the Bladder

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Abstract

Purpose

Recently, efficacy studies in mice have shown that amine-terminated cationic (CNP) nanoparticulate carriers of DTX offer an improved formulation of the drug for intravesical delivery. It is hypothesized that this improved efficacy may arise from a carrier mediated bladder exfoliation process that removes the urothelial barrier allowing for increased drug uptake into bladder tissue. The objective of this study was to investigate exfoliation processes in fresh pig’s bladders (ex vivo) exposed to three cationic polyglycerols with increasing degrees of amination (denoted 350, 580 and 780). The study also compared the tissue depth profile of DTX uptake into these tissues using these different carriers.

Materials and Methods

Aminated polyglycerols were synthesized and characterized in the laboratory with low (CNP-360), medium (CNP-580) and high (CNP-780) levels of amine content. CNP-based DTX solutions and commercial DTX solutions in polysorbate 80 (Taxotere®) were doped with 3H-radiolabeled DTX and prepared by solvent evaporation from acetonitrile, followed by drying and reconstitution in pH 6.4 buffer. Sections of fresh pig’s bladder tissue were clamped into Franz diffusion cells and the urothelial side was exposed to the DTX solutions for 2 h. Tissue sections were then frozen for sectioning by cryotome sectioning and subsequently processed for drug analysis by liquid scintillation counting. Alternatively tissue sections were fixed in 2% glutaraldehyde and 2% paraformaldehyde in 0.1 M sodium cacodylate buffer for the purposes of scanning electron microscopy (SEM).

Results

Exposure of the urothelial surface to the amine-terminated polyglycerol solutions resulted in the exfoliation of bladder tissues in a time- and concentration-dependent manner. Exfoliation was significantly more pronounced when using CNPs with a medium or high levels of amination whereas only minor levels of exfoliation were seen with low levels. Following incubation of tissues in Tween-based commercial formulations (Taxotere) of DTX (0.5 mg/mL) the drug was detectable at low levels (10–40 μg/g tissue) in all depths of tissue. Similar drug uptake was observed using the CNP-360 formulation. However drug uptake levels were increased to 60–100 μg/g tissue when samples were incubated with either the CNP-580 or CNP-780 formulations.

Conclusion

The use of cationic polyglycerols with higher levels of amine termination allows for an enhanced uptake of DTX into bladder tissues as compared to commercial (Taxotere) formulations. These increased drug levels probably arise from exfoliation processes resulting in a temporary elimination of the urothelial permeability barrier and increased drug penetration into the tissue.

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Abbreviations

CNP:

Cationic polyglycerol

CNP-C8/10-MePEG:

Hydrophobically modified CNPs with C8/C10 alkyl chains and Methoxy poly (ethylene glycol)

CNP-C8/10-MePEG-NH2 :

CNP-C8/10-MePEG with surface amine groups

DTX:

Docetaxel

NMIBC:

Non-muscle invasive bladder cancer

O/DEG:

Octyl/decyl glycidyl ether

PTX:

Paclitaxel

SEM:

Scanning electron microscopy

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Acknowledgements

The research work was funded by the Canadian Institute of Health and Research (CIHR). We thank the Centre for Drug and Research Development (CDRD) for providing the polymer and expertise that greatly assisted the research.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Science, The University of British Columbia, 2405 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada

    Rakhi Pandey, John K. Jackson & Helen M. Burt

  2. The Centre for Drug Research and Development, 2405 Wesbrook Mall, Fourth Floor, Vancouver, British Columbia, V6T 1Z2, Canada

    Clement Mugabe & Richard Liggins

Authors
  1. Rakhi Pandey
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  2. John K. Jackson
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  3. Clement Mugabe
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  4. Richard Liggins
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Corresponding author

Correspondence to Rakhi Pandey.

Additional information

In this research article amine group substitution on CNP’s is represented by the number of micromoles (x) of amine per gram of CNP’s and is denoted by CNP- (x) where x is 360 (low), 580 (medium) and 780 (high) μmoles of amine per gram of CNP.

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Pandey, R., Jackson, J.K., Mugabe, C. et al. Tissue Permeability Effects Associated with the Use of Mucoadhesive Cationic Nanoformulations of Docetaxel in the Bladder. Pharm Res 33, 1850–1861 (2016). https://doi.org/10.1007/s11095-016-1920-6

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  • DOI: https://doi.org/10.1007/s11095-016-1920-6

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