Data Sheet 1_Telodendrimer nanotrap for selective cytokine removal from sepsis patient plasma.docx

IntroductionSepsis remains difficult to treat, resulting in persistently high mortality, creating a significant clinical need for novel therapeutic approaches that provide precise immune modulation. A highly customizable telodendrimer nanotrap (TDNT) platform was developed to selectively remove inflammatory cytokines based on cytokine charge disparity and demonstrated improved survival in experimental murine sepsis. In this study, plasma from patients with abdominal sepsis was characterized for cytokine profiles and used to optimize the engineered TDNT resins for selective attenuation by targeting cytokine charge disparity.
MethodsTDNT resins were screened against a spiked mixture of patient plasma, and three lead formulations were identified with different cytokine binding profiles. The correlation between individual patient cytokine profiles and clinical diagnosis was studied. The cytokine removal efficacy of the lead candidates was subsequently validated using 20 individual sepsis patient plasma samples for comparison with a commercial macroporous hemoperfusion resin.
ResultsAfter screening patient plasma, we optimized three lead nanotrap resins to selectively absorb either positively charged or negatively charged cytokines or to target universal cytokine removal. Upon validation in individual sepsis patient plasma, the selective cytokine binding profiles of the lead selective nanotrap resins were confirmed; however, overall cytokine clearance efficacy was moderate. The pan-affinitive TDNT resin effectively removes cytokines from patient plasma with comparable efficiency to the commercial MG250® resin and significantly lower nonspecific adsorption of serum proteins, indicating more promising biocompatibility. A trend of correlation was observed between total cytokine levels in patient plasma and clinical Sequential Organ Failure Assessment (SOFA) score, as well as an inverse correlation with Systemic Immune-Inflammation Index (SII) score. Finally, the pan-affinitive TDNT resin was able to remove cytokines from patient plasma regardless of patient SOFA or SII score and effectively reduced the overall cytokine burden to levels that correlate with reduced mortality risk.
ConclusionTargeting cytokine charge disparity and total cytokine burden using TDNT resins with different cytokine binding profiles is promising for effectively addressing the dysregulated immune response in sepsis and reducing mortality, which warrants further testing in a large cohort of patients.