Verifying Engineering at the Nanoscale

Electron Microscopy and Drug Delivery

Nov. 01, 2008

Fig. 1: Amphiphilic polymers and dendrimers used to make self assembling drug and gene delivery systems respectively.

Fig. 1: Amphiphilic polymers and dendrimers used to make self assembling drug and gene delivery ... more

Packaging drugs and genes into nanoparticles enables drug or gene biodistribution to be favourably altered, with an ultimate therapeutic benefit [1-3]. To acquire such control on the in vivo fate of drugs and genes requires that such particles be precision engineered and electron microscopy is one of the techniques used to visualise and confirm the results of such engineering.

Methods

Pharmaceutical nanosystems in our laboratory have been prepared from the self assembly of: a) comb type polymers [4-6] and b) dendrimers [7, 8] (fig. 1). By exercising control on the chemistry of these self assembling molecules, a variety of functional nanosystems may be prepared. Applying physical characterisation techniques including imaging to the resulting self assemblies and studying their in vivo behaviour ultimately enables robust correlations to be made between polymer chemistry, nature of the self assembly and drug delivery performance.

Results

Self assembling comb type polymers have been prepared from carbohydrates [2, 5], polyamino acids [4] and polyamines [1, 6] and altering the level of hydrophobic substitution alters the nature of the self assembly (fig. 2). Additionally we have identified two chemical features of these amphiphilic polymers which control nanosystem size (and ultimately nanosystem biodistribution) and these are the molecular weight of the polymer [5] and the level of hydrophobic substitution of the polymer [6], both of which are positively and linearly correlated with nanosystem size (e.g. fig. 3).
Carbohydrate micellar clusters, in which one micelle is linked to another, presumably via trailing polymer chains are able to form nanoparticles in the presence of hydrophobic drugs [2]. These drug loaded nanoparticles increase drug bioavailability across the blood brain barrier by up to ten fold when compared to the current state of the art commercial emulsion system (fig. 4) [2]. Amphiphilic polyamine drug loaded nanoparticles increase drug absorption via the oral route by up to three fold when compared to the drug suspension in water [1]. Additionally polypropylenimine dendrimers form colloidal particles with DNA which are able to transfer an anti-proliferative gene, the tumour necrosis alpha gene, into mouse tumours and produce a 100 % response in all tumours studied, due in part to the additional anti-proliferative activity of the dendrimer [3].

Conclusions

It is possible to correlate polymer chemistry with the nature of the resulting self assembly and ultimately link a range of morphologically distinct nano-size self assemblies with specific drug delivery function.

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With these nanosystems, a ten fold increase in drug activity may be obtained [2] and an effective anti-cancer gene medicine is achievable [3].

References:
[1] Cheng, W., et al., Biomacromolecules, 7, 1509-1520 (2006)
[2] Qu, X., et al., Biomacromolecules, 7, 3452-3459 (2006)
[3] Dufes, C., et al., Cancer Research, 65, 8079-8084 (2005)
[4] Wang, W., et al., Langmuir, 16, 7859-7866 (2000)
[5] Wang, W., et al., Langmuir, 17, 631-636 (2001)
[6] Wang, W., et al., Macromolecules, 37, 9114-9122 (2004)
[7] Zinselmeyer, B. H., et al., Pharmaceutical Research, 19, 960-967 (2002)
[8] Schätzlein, A. G., et al., J. Control. Rel., 101, 247-258 (2005)

Authors:
Ijeoma F. Uchegbu

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