Abstract
PurposeThe objective of this work was to evaluate the potential of polymeric spherical and aspherical invasive nanocarriers, loaded with antibiotic, to access and treat intracellular bacterial infections.MethodsAspherical nanocarriers were prepared by stretching of spherical precursors, and both aspherical and spherical nanocarriers were surface-functionalized with the invasive protein InvA497. The relative uptake of nanocarriers into HEp-2 epithelial cells was then assessed. Nanocarriers were subsequently loaded with a preparation of the non-permeable antibiotic gentamicin, and tested for their ability to treat HEp-2 cells infected with the enteroinvasive bacterium Shigella flexneri.ResultsInvA497-functionalized nanocarriers of both spherical and aspherical shape showed a significantly improved rate and extent of uptake into HEp-2 cells in comparison to non-functionalized nanocarriers. Functionalized and antibiotic-loaded nanocarriers demonstrated a dose dependent killing of intracellular S. flexneri. A slight but significant enhancement of intracellular bacterial killing was also observed with aspherical as compared to spherical functionalized nanocarriers at the highest tested concentration.ConclusionsInvA497-functionalized, polymer-based nanocarriers were able to efficiently deliver a non-permeable antibiotic across host cell membranes to affect killing of intracellular bacteria. Functionalized nanocarriers with an aspherical shape showed an interesting future potential for intracellular infection therapy.
Highlights
While delivery of anti-infective drugs using nanocarriers is an attractive option for the treatment of infections, several factors may act to limit the efficacy of this strategy
InvA497 [8]; gentamicin-loaded liposomes surface functionalized with InvA497 were further demonstrated to be able to reach and kill intracellular bacteria located in various epithelial sub-cellular compartments [3,9]
A small but significant improvement of bacterial killing was seen with AsphIG as compared to SphIG at the highest employed dose (Fig. 7b). This difference indicates a promising application of shape-modified InvA497-functionalized carrier systems for intracellular infection treatment; the modest magnitude of this difference highlights the considerable remaining scope for carrier system development and probing of shape effects – namely, optimization of aspect ratio and maintenance of asphericity in order to further enhance intracellular bacterial killing. These results demonstrate that the presence of InvA497 on the surface of polymer-based nanocarriers in combination with encapsulation of AOTgentamicin is able to increase the ability of the delivery system to effectively treat infected epithelial cells
Summary
While delivery of anti-infective drugs using nanocarriers is an attractive option for the treatment of infections, several factors may act to limit the efficacy of this strategy. Incorporation of drug candidates into particulate nanocarriers functionalized with invasive moieties to enhance cellular uptake is a potential way to overcome this delivery problem. In this respect, the use of bacterial proteins which naturally mediate the invasion of bacteria into mammalian cells has been reported as a promising means of enhancing the permeation of carrier systems, and potentially increasing the intracellular efficacy of their drug loads [3,4,5,6]. A interesting candidate in this category is invasin, a well-characterized outer membrane invasion protein expressed on the surface of Yersinia pseudotuberculosis and Yersinia enterocolitica, which mediates an efficient entry of the bacteria into eukaryotic cells through interaction with β1 integrin receptors [7,8]. Dersch et al were able to produce and purify such a C-terminal, cell-invasive fragment of invasin, referred to as
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