Animal "avatars" and co-clinical trials are being developed for possible use in personalized medicine in oncology. In a co-clinical trial, the cancer cells of the patient's tumor are xenotransplanted into the animal avatar for drug efficacy studies, and the data collected in the animal trial are used to plan the best drug treatment in the patient trial. Zebrafish have recently been proposed for implementing avatar models, however the lack of a general criterion for the chemotherapy dose conversion from humans to fish is a limitation in terms of conducting co-clinical trials. Here, we validate a simple, reliant and cost-effective avatar model based on the use of zebrafish embryos. By crossing data from safety and efficacy studies, we found a basic formula for estimating the equivalent dose for use in co-clinical trials which we validated in a clinical study enrolling 24 adult patients with solid cancers (XenoZ, NCT03668418).

24Animal ''Avatars'' and co-clinical trials represent an emerging concept for 25 implementing schemes of personalized medicine in oncology. In a co-clinical 26 trial, the cancer cells of the patient tumor are xenotransplanted in the animal 27 Avatar for drug efficacy studies and data collected in the animal trial are used 28 to plan the best drug treatment in the patient trial. Recently, zebrafish has 29 been proposed for implementing Avatar models but the lack of a general 30 criterion for chemotherapy dose conversion from humans to fishes represents 31 a limitation for conducting co-clinical trials. 32Here, we validate a simple, reliant and cost-effective Avatar model based on 33 the use of zebrafish larvae; by crossing data from safety and efficacy studies, 34 we found a basic formula for the estimation of the dose to be used for running 35 co-clinical trials and we validate it in a clinical study enrolling 24 adult patients 36 with solid cancers (XenoZ, NCT03668418). 37 ABBREVIATIONS 38 5-FU, 5-Fluorouracil; dpf, days post fertilization; DMEM, Dulbecco's modified 39 Eagle's medium; FBS, fetal bovine serum; ECF, 5-Fluorouracil + Cisplatin + 40 Epirubicin; FLOT, 5-Fluorouracil + Lederfolin + Oxaliplatin + Docetaxel; 41 FOLFIRI, 5-Fluorouracil + Lederfolin + Irinotecan; FOLFOX, 5-Fluorouracil + 42 Lederfolin + Oxaliplatin; FOLFOXIRI, 5-Fluorouracil + Lederfolin + Oxaliplatin 43 + Irinotecan; GEM, Gemcitabine; GEMCIS, Gemcitabine + Cisplatin; 44 GEM/nab-P, Gemcitabine + nab-Paclitaxel; GEMOX, Gemcitabine + 45 Oxaliplatin; hpf, hours post fertilization; hpi, hours post injection 48Precision medicine refers to the approaches for tailoring a medical treatment 49 to the individual characteristics of each patient (1). In particular, the "Mouse 50 Avatar" is an emerging approach of precision medicine in oncology that has 51 recently grown in importance (2); it implicates the xenotransplantation of 52 cancer cells from patient tumor sample in mouse models to use them in drug 53 efficacy studies. Mouse Avatars can be used to run "co-clinical trials" (3). In a 54 co-clinical trial, the patient and murine trials are concurrently conducted and 55 the drug efficacy response of the mouse study provides data to plan the best 56 drug treatment of the patient tumor (4). The advantage of this approach is that 57 each patient has his/her own tumor growing in an in vivo system, thereby 58 allowing the identification of a personalized therapeutic approach. Nowadays, 59 there are companies providing mouse Avatar generation and drug testing 60 services to patients at a cost of tens thousands of dollars (5). The high cost is 61 directly associated to the time-consuming process and the requirement of 62 immunosuppressed strains (6). Unfortunately, this makes Avatars a cutting-63 edge technology available only for few people, posing a serious threat to the 64 equal right to health for everyone. Recently, it has been proposed the use of 65 zebrafish to make Avatars available for every patient and the approach 66 sustainable for N...

Neuroprotective drug delivery to the posterior segment of the eye represents a major challenge to counteract vision loss. This work focuses on the development of a polymer-based nanocarrier, specifically designed for targeting the posterior eye. Polyacrylamide nanoparticles (ANPs) were synthesised and characterised, and their high binding efficiency was exploited to gain both ocular targeting and neuroprotective capabilities, through conjugation with peanut agglutinin (ANP:PNA) and neurotrophin nerve growth factor (ANP:PNA:NGF). The neuroprotective activity of ANP:PNA:NGF was assessed in an oxidative stress-induced retinal degeneration model using the teleost zebrafish. Upon nanoformulation, NGF improved the visual function of zebrafish larvae after the intravitreal injection of hydrogen peroxide, accompanied by a reduction in the number of apoptotic cells in the retina. Additionally, ANP:PNA:NGF counteracted the impairment of visual behaviour in zebrafish larvae exposed to cigarette smoke extract (CSE). Collectively, these data suggest that our polymeric drug delivery system represents a promising strategy for implementing targeted treatment against retinal degeneration.