SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species.

Background: SQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC™) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors ( NCT04106492 ) demonstrating SQ3370's activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity. Methods: Treatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors. Results: SQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370's safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3 + and CD8 + T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment. Conclusions: SQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development. Trial registration: NCT04106492; 7 September 2019.

Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation.

A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The CAPAC platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)-modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapies. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose (MTD) of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was determined to be 19.1-times the MTD of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the MTD of conventional doxorubicin with greatly reduced systemic toxicity. Finally, combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice.

Correction: Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation.

[This corrects the article DOI: 10.1039/D0SC06099B.].

Linguistic Z-number weighted averaging operators and their application to portfolio selection problem.

Z-numbers can generate a more flexible structure to model the real information because of capturing expert's reliability. Moreover, various semantics can flexibly be reflected by linguistic terms under various circumstances. Thus, this study aims to model the portfolio selection problems based on aggregation operators under linguistic Z-number environment. Therefore, a multi-stage methodology is proposed and linguistic Z-numbers are applied to describe the assessment information. Moreover, the weighted averaging (WA) aggregation operator, the ordered weighted averaging (OWA) aggregation operator and the hybrid weighted averaging (HWA) aggregation operator are developed to fuse the input arguments under the linguistic Z-number environment. Then, using the max-score rule and the score-accuracy trade-off rule, three qualitative portfolio models are presented to allocate the optimal assets. These models are suitable for general investors and risky investors. Finally, to illustrate the validity of the proposed qualitative approach, a real case including 20 corporations of Tehran stock exchange market in Iran is provided and the obtained results are analyzed. The results show that combining linguistic Z-numbers with portfolio selection processes can increase the tendencies and capabilities of investors in the capital market and it helps them manage their portfolios efficiently.

Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS.

The present study was designed to characterize transduction of non-human primate brain and spinal cord with a modified adeno-associated virus serotype 2, incapable of binding to the heparan sulfate proteoglycan receptor, referred to as AAV2-HBKO. AAV2-HBKO was infused into the thalamus, intracerebroventricularly or via a combination of both intracerebroventricular and thalamic delivery. Thalamic injection of this modified vector encoding GFP resulted in widespread CNS transduction that included neurons in deep cortical layers, deep cerebellar nuclei, several subcortical regions, and motor neuron transduction in the spinal cord indicative of robust bidirectional axonal transport. Intracerebroventricular delivery similarly resulted in widespread cortical transduction, with one striking distinction that oligodendrocytes within superficial layers of the cortex were the primary cell type transduced. Robust motor neuron transduction was also observed in all levels of the spinal cord. The combination of thalamic and intracerebroventricular delivery resulted in transduction of oligodendrocytes in superficial cortical layers and neurons in deeper cortical layers. Several subcortical regions were also transduced. Our data demonstrate that AAV2-HBKO is a powerful vector for the potential treatment of a wide number of neurological disorders, and highlight that delivery route can significantly impact cellular tropism and pattern of CNS transduction.

Interactive iBook-Based Patient Education in a NeuroTrauma Clinic.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Educational interventions may alleviate the burden of TBI for patients and their families. Interactive modalities that involve engagement with the educational material may enhance patient knowledge acquisition when compared to static text-based educational material. OBJECTIVE: To determine the effects of educational interventions in the outpatient setting on self-reported patient knowledge, with a focus on iPad-based (Apple, Cupertino, California) interactive modules. METHODS: Patients and family members presenting to a NeuroTrauma clinic at a tertiary care academic medical center completed a presurvey assessing baseline knowledge of TBI or concussion, depending on the diagnosis. Subjects then received either an interactive iBook (Apple) on TBI or concussion, or an informative pamphlet with identical information in text format. Subjects then completed a postsurvey prior to seeing the neurosurgeon. RESULTS: All subjects (n = 152) significantly improved on self-reported knowledge measures following administration of either an iBook (Apple) or pamphlet (P < .01, 95% confidence interval [CI]). Subjects receiving the iBook (n = 122) performed significantly better on the postsurvey (P < .01, 95% CI), despite equivalent presurvey scores, when compared to those receiving pamphlets (n = 30). Lastly, patients preferred the iBook to pamphlets (P < .01, 95% CI). CONCLUSION: Educational interventions in the outpatient NeuroTrauma setting led to significant improvement in self-reported measures of patient and family knowledge. This improved understanding may increase compliance with the neurosurgeon's recommendations and may help reduce the potential anxiety and complications that arise following a TBI.

Interactive eBooks in educating patients and their families about head injury regardless of age.

OBJECTIVES: Traumatic Brain Injury (TBI) is a common and debilitating injury that is particularly prevalent in patients over 60. Given the influence of head injury on dementia (and vice versa), and the increased likelihood of ground-level falls, elderly patients are vulnerable to TBI. Educational interventions can increase knowledge and influence preventative activity to decrease the likelihood of further TBI. We sought to determine the efficacy of interactive tablet-based educational interventions in elderly patients on self-reported knowledge. PATIENTS AND METHODS: Patients and family members, ages 20-90, presenting to a NeuroTrauma clinic completed a pre-survey to assess baseline TBI or concussion knowledge, depending on their diagnosis. Participants then received an interactive electronic book (eBook), or a text-based pamphlet with identical information, and completed a post-survey to test interim knowledge improvement. RESULTS: All participants (n=180), regardless of age, had significantly higher post-survey scores (p<0.01, 95% CI). Elderly participants who received the eBook (n=39) scored lower than their younger counterparts despite higher pre-survey scores (p<0.01, 95% CI). All participants who received the eBook (n=20, 90) significantly improved on the post-survey (p<0.01, 95% CI) when compared to participants who received the paper pamphlets (n=10, 31). All participants significantly preferred the eBook (p<0.01, 95% CI). CONCLUSIONS: We demonstrated that interactive educational interventions are effective in the elderly TBI population. Enhanced educational awareness in the elderly population, especially patients at risk or with prior TBI, may prevent further head injury by educating patients on the importance of avoiding further head injury and taking precautionary measures to decrease the likelihood of further injury.