Fig. 3: In vivo ketamine AAL uncaging at functionally relevant regions. | Nature Nanotechnology

Fig. 3: In vivo ketamine AAL uncaging at functionally relevant regions.

From: Acoustically activatable liposomes as a translational nanotechnology for site-targeted drug delivery and noninvasive neuromodulation

Fig. 3

a, Top: rats received 1.5 mg kg−1 intravenous of ketamine-loaded AALs (S5-KL from prior, now SonoKet; n = 3) or dose-matched KetHCl (n = 3) for 5 min, with sonication (FUS) at t = 2.5–5.0 min or no sonication (n = 5). Bottom: simulated (Extended Data Fig. 3) ultrasound beamplots overlaid onto mPFC (mediates affective ketamine responses) or RsC (mediates dissociative ketamine responses) targets (sagittal brain drawings made new for this figure with cross-reference to the Paxinos atlas43 to ensure accuracy). SPME sampling targets indicated as white asterisk = sonication on, black asterisk = no sonication with sampling every 5 min for 25 min post-infusion start. b, Initial ketamine levels show higher ketamine from both mPFC and RsC with SonoKet sonication versus KetHCl or SonoKet without sonication. mPFC: KetHCl versus SonoKet (P = 0.0028, Hedges g = 3.66); KetHCl + FUS versus SonoKet + FUS (P = 0.0041, Hedges g = 3.24); SonoKet versus SonoKet + FUS (P = 7 × 10−6, Hedges g = 7.31). RsC: KetHCl versus SonoKet (P = 0.0016, Hedges g = 45.46); KetHCl + FUS versus SonoKet + FUS (P = 0.0018, Hedges g = 2.69); SonoKet versus SonoKet + FUS (P = 2.99 × 10−5, Hedges g = 5.37). One-way, two-sided, ANOVA and Tukey’s post hoc HSD, *P < 0.05, **P < 0.01, ***P < 0.001 and ****P < 0.0001. c, No difference in pharmacodistribution or pharmacokinetics of ketamine or norketamine with free ketamine and sonication at either target. Hydroxynorketamine levels below limit of detection. Paired t-tests, two-sided. d, Ketamine and norketamine brain levels and clearance with SonoKet show higher brain ketamine with sonication applied to mPFC (top left; 5 min, P = 0.0043, 10 min, P = 0.0057) or RsC (middle left; 5 min, P = 0.010, 10 min, P = 0.022) versus non-sonicated regions. Similar clearance rate in both regions. Hydroxynorketamine levels below limit of detection. Paired t-tests, two-sided, *P < 0.05 and **P < 0.01. e, Blood pharmacokinetics of ketamine, norketamine and hydroxynorketamine; modelling results in Extended Data Table 3. Paired t-tests, two-sided. Data presented as mean ± s.d.

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