Cyclodextrin/adamantane-mediated targeting of inoculated bacteria in mice

Welling, M.M.; Duszenko, N.; Willigen, D.M. van; Smits, W.K.; Buckle, T.; Roestenberg, M.; Leeuwen, F.W.B. van

doi:doi:10.1021/acs.bioconjchem.1c00061

Cyclodextrin (CD)-based host-guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells in vitro. The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells in vivo, e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent Staphylococcus aureus models. Bacteria (1 X 10(8) viable S. aureus) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with Tc-99m-UBI29-41-Ad(2) (primary vector), which allowed us to both determine the bacterial load and create an in vivo target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a In-111-Cy5(0)(.5)CD(9)PIBMA(39 )polymer that was administered intravenously. Bacteria-specific cargo delivery as a result of...Show moreCyclodextrin (CD)-based host-guest interactions with adamantane (Ad) have demonstrated use for functionalizing living cells in vitro. The next step in this supramolecular functionalization approach is to explore the concept to deliver chemical cargo to living cells in vivo, e.g., inoculated bacteria, in order to study their dissemination. We validated this concept in two rodent Staphylococcus aureus models. Bacteria (1 X 10(8) viable S. aureus) were inoculated by (1) intramuscular injection or (2) intrasplenic injection followed by dissemination throughout the liver. The bacteria were prefunctionalized with Tc-99m-UBI29-41-Ad(2) (primary vector), which allowed us to both determine the bacterial load and create an in vivo target for the secondary host-vector (24 h post-inoculation). The secondary vector, i.e., chemical cargo delivery system, made use of a In-111-Cy5(0)(.5)CD(9)PIBMA(39 )polymer that was administered intravenously. Bacteria-specific cargo delivery as a result of vector complexation was evaluated by dual-isotope SPECT imaging and biodistribution studies (In-111), and by fluorescence (Cy5); these evaluations were performed 4 h post-injection of the secondary vector. Mice inoculated with nonfunctionalized S. aureus and mice without an infection served as controls. Dual-isotope SPECT imaging demonstrated that In-111-Cy5(0)(.5)CD(9)PIBMA(3)(9) colocalized with Tc-99m-UBI29-41-Ad(2)-labeled bacteria in both muscle and liver. In inoculated muscle, a 2-fold higher uptake level (3.2 +/- 1.0%ID/g) was noted compared to inoculation with nonfunctionalized bacteria (1.9 +/- 0.4%ID/g), and a 16-fold higher uptake level compared to noninfected muscle (0.2 +/- 0.1%ID/g). The hepatic accumulation of the host-vector was nearly 10-fold higher (27.1 +/- 11.1%ID/g) compared to the noninfected control (2.7 +/- 0.3%ID/g; p < 0.05). Fluorescence imaging of the secondary vector corroborated SPECT-imaging and biodistribution findings. We have demonstrated that supramolecular host-guest complexation can be harnessed to achieve an in vivo cargo delivery strategy, using two different bacterial models in soft tissue and liver. This proof-of-principle study paves a path toward developing innovative drug delivery concepts via cell functionalization techniques.Show less

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Cyclodextrin/adamantane-mediated targeting of inoculated bacteria in mice