In silico multiscale computational modelling of botulinum toxin a diffusion for glabellar wrinkle treatment: Optimizing injection volumes across formulations

IF 2.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Eqram Rahman , Jean D.A. Carruthers , Parinitha Rao , Munim Ahmed , Greg J. Goodman , William Richard Webb
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引用次数: 0

Abstract

While botulinum neurotoxin A (BoNT/A) is a cornerstone in glabellar wrinkle treatment, inconsistencies in clinical outcomes often stem from formulation-dependent diffusion behaviour. Currently volumes recommendation per site lacks mechanistic justification, especially in anatomically confined regions like the glabella, where millimetric diffusion differences can produce significant adverse effects. A high-fidelity, multiscale in silico platform was developed, integrating quantum mechanical (TD-DFT) modelling of SV2-binding (ΔG_bind range: −9.2 to −11.7 kcal/mol), molecular dynamics-derived hydrodynamic radius (R_H: 9.4–11.2 nm), anisotropic finite element modelling of poroelastic muscle tissue, and agent-based receptor and immune kinetics. Simulations encompassed five formulations— AbobotulinumtoxinA (ABO), DaxibotulinumtoxinA (DAXI), IncobotulinumtoxinA (INCO), OnabotulinumtoxinA (ONA), and PrabotulinumtoxinA (PRABO)—across injection volumes from 0.025 to 0.1 mL, at fixed toxin unit dosing, within anatomically realistic glabellar meshes (n = 10,000 synthetic patient variants). Diffusion profiles varied significantly by formulation. ABO showed the largest Reff (1.64 ± 0.14 cm) and E_off, while PRABO and ONA remained spatially constrained (Reff = 0.96 ± 0.07 cm and 1.13 ± 0.08 cm, respectively). Increasing injection volume from 0.025 to 0.1 mL caused a 2.2-fold rise in E_off and a 36–49 % increase in off-target V_IC50 across formulations. Optimal containment was formulation-specific: PRABO and ONA achieved ≥95 % V_IC90 coverage with <10 % V_IC50 spillover at 0.025–0.035 mL; INCO and DAXI required 0.035–0.05 mL; ABO balanced broader coverage with acceptable diffusion at 0.04–0.045 mL. Agent-based models revealed 78 % receptor saturation at 0.025 mL versus 56 % at 0.1 mL, with immune clearance rates up to 42 % higher at high volumes due to increased perivascular redistribution. Volume emerged as the dominant spread driver (Sobol S1 = 0.48), followed by hydrodynamic radius (S1 = 0.35) and macrophage density (S1 = 0.28); interaction terms were negligible (S_T − S1 < 0.05). This study provides the first in-silico quantitative, multiscale evidence that reducing BoNT/A reconstitution volume to ≤0.045 mL/site significantly enhances target localization while minimizing off-target effects. Contrary to prevailing clinical heuristics, dilution amplifies mechanical spread and immune clearance risk.

Abstract Image

在硅多尺度计算模拟肉毒杆菌毒素扩散为眉间皱纹治疗:优化注射量跨配方
虽然肉毒杆菌神经毒素A (BoNT/A)是治疗眉间皱纹的基石,但临床结果的不一致往往源于配方依赖的扩散行为。目前,每个部位的推荐量缺乏机制依据,特别是在解剖学受限的区域,如眉间,毫米扩散差异会产生显著的不良反应。开发了一个高保真,多尺度的硅平台,集成了sv2结合的量子力学(TD-DFT)模型(ΔG_bind范围:−9.2至−11.7 kcal/mol),分子动力学衍生的流体动力学半径(R_H: 9.4-11.2 nm),多孔弹性肌肉组织的各向异性有限元模型,以及基于药物的受体和免疫动力学。模拟包括五种配方-肉毒杆菌毒素(ABO), DAXI肉毒杆菌毒素(DAXI), incobobotulintoxina (INCO), OnabotulinumtoxinA (ONA)和prabotulintoxina (PRABO) -注射体积从0.025到0.1 mL,以固定的毒素单位剂量,在解剖学上真实的小梁网内(n = 10,000合成患者变异)。扩散曲线因配方不同而有显著差异。ABO的Reff(1.64±0.14 cm)和E_off最大,而PRABO和ONA的Reff(分别为0.96±0.07 cm和1.13±0.08 cm)受空间约束。将注射量从0.025增加到0.1 mL,各剂型的E_off增加2.2倍,脱靶V_IC50增加36 - 49%。最佳遏制是针对处方的:PRABO和ONA在0.025-0.035 mL时达到≥95%的V_IC90覆盖率,10%的V_IC50溢出;INCO和DAXI要求0.035-0.05 mL;ABO在0.04-0.045 mL可接受的扩散范围内平衡了更广泛的覆盖范围。基于试剂的模型显示,在0.025 mL时受体饱和度为78%,而在0.1 mL时为56%,由于血管周围再分布增加,高容量时免疫清除率高达42%。体积是主要的扩散驱动因素(Sobol S1 = 0.48),其次是流体动力半径(S1 = 0.35)和巨噬细胞密度(S1 = 0.28);相互作用项可以忽略不计(S_T−S1 < 0.05)。该研究首次提供了硅定量、多尺度证据,证明将BoNT/A重构体积降低至≤0.045 mL/位点可显著增强靶标定位,同时最大限度地减少脱靶效应。与流行的临床启发式相反,稀释放大了机械扩散和免疫清除风险。
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来源期刊
Toxicon
Toxicon 医学-毒理学
CiteScore
4.80
自引率
10.70%
发文量
358
审稿时长
68 days
期刊介绍: Toxicon has an open access mirror Toxicon: X, sharing the same aims and scope, editorial team, submission system and rigorous peer review. An introductory offer Toxicon: X - full waiver of the Open Access fee. Toxicon''s "aims and scope" are to publish: -articles containing the results of original research on problems related to toxins derived from animals, plants and microorganisms -papers on novel findings related to the chemical, pharmacological, toxicological, and immunological properties of natural toxins -molecular biological studies of toxins and other genes from poisonous and venomous organisms that advance understanding of the role or function of toxins -clinical observations on poisoning and envenoming where a new therapeutic principle has been proposed or a decidedly superior clinical result has been obtained. -material on the use of toxins as tools in studying biological processes and material on subjects related to venom and antivenom problems. -articles on the translational application of toxins, for example as drugs and insecticides -epidemiological studies on envenoming or poisoning, so long as they highlight a previously unrecognised medical problem or provide insight into the prevention or medical treatment of envenoming or poisoning. Retrospective surveys of hospital records, especially those lacking species identification, will not be considered for publication. Properly designed prospective community-based surveys are strongly encouraged. -articles describing well-known activities of venoms, such as antibacterial, anticancer, and analgesic activities of arachnid venoms, without any attempt to define the mechanism of action or purify the active component, will not be considered for publication in Toxicon. -review articles on problems related to toxinology. To encourage the exchange of ideas, sections of the journal may be devoted to Short Communications, Letters to the Editor and activities of the affiliated societies.
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