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Multidrug resistance (MDR) reduces the efficacy of chemotherapy. Besides inducing the expression of drug efflux pumps, chemotherapy treatment alters the composition of the tumor microenvironment (TME), thereby potentially limiting tumor-directed drug delivery. To study the impact of MDR signaling in cancer cells on TME remodeling and nanomedicine delivery, we generated multidrug-resistant 4 T1 triple-negative breast cancer (TNBC) cells by exposing sensitive 4 T1 cells to gradually increasing doxorubicin concentrations. In 2D and 3D cell cultures, resistant 4 T1 cells presented with a more mesenchymal phenotype and produced increased amounts of collagen. While sensitive and resistant 4 T1 cells showed similar tumor growth kinetics in vivo, the TME of resistant tumors was enriched in collagen and fibronectin. Vascular perfusion was also significantly increased. Fluorophore-labeled polymeric (~10 nm) and liposomal (~100 nm) drug carriers were administered to mice with resistant and sensitive tumors. Their tumor accumulation and penetration were studied using multimodal and multiscale optical imaging. At the whole tumor level, polymers accumulate more efficiently in resistant than in sensitive tumors. For liposomes, the trend was similar, but the differences in tumor accumulation were insignificant. At the individual blood vessel level, both polymers and liposomes were less able to extravasate out of the vasculature and penetrate the interstitium in resistant tumors. In a final in vivo efficacy study, we observed a stronger inhibitory effect of cellular and microenvironmental MDR on liposomal doxorubicin performance than free doxorubicin. These results exemplify that besides classical cellular MDR, microenvironmental drug resistance features should be considered when aiming to target and treat multidrug-resistant tumors more efficiently.

Tissue engineering and regenerative medicine (2022). doi:10.1007/s13770-022-00482-0, Published by Springer, Heidelberg

Microbubbles (MB) are used as ultrasound (US) contrast agents and can be efficiently targeted against markers of angiogenesis and inflammation. Due to their gas core, MB locally alter susceptibilities in magnetic resonance imaging (MRI), but unfortunately, the resulting contrast is low and not sufficient to generate powerful molecular MRI probes. Therefore, we investigated whether a potent molecular MR agent can be generated by encapsulating superparamagnetic iron oxide nanoparticles (SPION) in the polymeric shell of poly (n-butylcyanoacrylate) (PBCA) MB and targeted them against α vβ3 integrins on the angiogenic vasculature of 4T1 murine breast carcinomas. SPION-MB consist of an air core and a multi-layered polymeric shell enabling efficient entrapment of SPION. The mean size of SPION-MB was 1.61 ± 0.32 μm. Biotin-streptavidin coupling was employed to functionalize the SPION-MB with cyclic RGDfK (Arg-Gly-Asp) and RADfK (Arg-Ala-Asp) peptides. Cells incubated with RGD-SPION-MB showed enhanced transverse relaxation rates compared with SPION-MB and blocking α vβ3 integrin receptors with excess free cRGDfK significantly reduced RGD-SPION-MB binding. Due to the fast binding of RGD-SPION-MB in vivo , dynamic susceptibility contrast MRI was employed to track their retention in tumors in real-time. Higher retention of RGD-SPION-MB was observed compared with SPION-MB and RAD-SPION-MB. To corroborate our MRI results, molecular US was performed the following day using the destruction-replenishment method. Both imaging modalities consistently indicated higher retention of RGD-SPION-MB in angiogenic vessels compared with SPION-MB and RAD-SPION-MB. Competitive blocking experiments in mice further confirmed that the binding of RGD-SPION-MB to α vβ3 integrin receptors is specific. Overall, this study demonstrates that RGD-SPION-MB can be employed as molecular MR/US contrast agents and are capable of assessing the αvβ3 integrin expression in the neovasculature of malignant tumors.

Background Efficacy of SC abatacept (ABA) in patients (pts) with polyarticular-course juvenile idiopathic arthritis (pJIA) was shown in a 2-year, open-label, Phase III international study (NCT01844518).1 Restricted growth and delayed puberty are associated with pJIA;2 however, the effect of ABA on growth and development is unknown. Objectives To investigate the effect of ABA on height, BMI and Tanner staging, and to assess the impact of BMI on ABA efficacy in pts with pJIA. Methods Patients with pJIA were grouped into two age cohorts (2–5 and 6–17 years [yrs]) and received weight-tiered SC ABA (10 to −2 to ≤1), overweight (>1 to ≤2) and obese (>2) (intent-to-treat, non-responder imputation for missing efficacy data). In the 6–17-yr cohort, Tanner staging was recorded at BL and at discontinuation or completion of study. Results Data for standardised height and BMI are presented. In 6–17-yr-old pts with BL Tanner stage ≤3 (n=100), BL mean (SD) height was −0.53 (1.53); at D645, mean (95% CI) change was 0.20 (0.06, 0.34; Figure 1). In 6–17-yr-old pts with a BL height ≤−1 (n=42), BL mean (SD) height was −2.10 (1.01) and mean (95% CI) change at D645 was 0.49 (0.23, 0.76). In 2–5-yr-old pts, BL mean (SD) height was 0.07 (1.37); at D645, mean (95% CI) change was 0.13 (−0.09, 0.36). In 13 pts aged 6–17 yrs of the lowest height (Tanner stage ≤3 and BL height ≤−2), mean (SD) height increased from −3.28 (1.10) at BL to −2.59 (1.31) by D645. At BL, mean (SD) BMI was 0.20 (1.33) in the 6–17-yr cohort (n=173) and 0.25 (1.57) in the 2–5-yr cohort (n=46); at D645, mean (95% CI) change in BMI was 0.02 (−0.13, 0.16; Figure 2) and 0.17 (−0.08, 0.42), respectively. Overall, no relationship was seen between change from BL in Juvenile Arthritis Disease Activity Score 71 (JADAS71) and BL BMI in either age cohort. The proportions (odds ratio [OR]; 95% CI of OR) of obese pts aged 6–17 yrs achieving JIA-ACR30 (0.15; 0.04, 0.55), JIA-ACR50 (0.18; 0.05, 0.63), JIA-ACR70 (0.17; 0.04, 0.67) and JADAS71 minimal disease activity (0.27; 0.07, 1.03) at Day 645 were significantly lower compared with pts with a normal BMI, but the sample size in the obese category was low (n=12); this effect was not seen in overweight pts (n=37). In female pts (n=92), shifts in Tanner stages from BL to D645 were as expected; male sexual maturation was difficult to assess due to the small sample size (n=20). Conclusion Abatacept improves growth and development in pts with pJIA. Early therapeutic intervention with abatacept may help reduce growth restrictions in pts with pJIA. BMI may impact the efficacy response, resulting in lower efficacy in obese, but not in overweight, pts with pJIA versus pts with normal BMI. References [1] Brunner HI, et al. Arthritis Rheumatol2018;70:1144–54. [2] Umlawska W, et al. Arch Med Sci2010;6:19–23. Acknowledgement Professional medical writing: Lola Parfitt, MRes, Caudex; funding: Bristol-Myers Squibb Disclosure of Interests Nicolino Ruperto Grant/research support from: The Gaslini Hospital, where NR works as full-time public employee, has received contributions (> 10.000 USD each) from the following industries in the last 3 years: BMS, Eli-Lilly, GlaxoSmithKline, F Hoffmann-La Roche, Janssen, Novartis, Pfizer, Sobi. This funding has been reinvested for the research activities of the hospital in a fully independent manner, without any commitment with third parties., Consultant for: Received honoraria for consultancies or speaker bureaus ( I perform consultancy activities on behalf of the Gaslini Institute for the companies listed below: AbbVie, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm. The money received for these activities are directly transferred to the Gaslini Institute’s bank account. Before March 2016, I was the head of the Pediatric Rheumatology Department at the G. Gaslini Hospital, where the PRINTO Coordinating Centre is located. For the coordination activity of the PRINTO network, the Gaslini Hospital received contributions from the industries listed in this section. This money has been reinvested for the research activities of the hospital in fully independent manners besides any commitment with third parties., Daniel J Lovell Consultant for: Consulting fees and/or honoraria from Astra Zeneca, Wyeth Pharma, Amgen, Abbott, Pfizer, F. Hoffmann-La Roche, Novartis, UBC, Takeda, GSK, Boehringer, and Celgene

Background Infections are the most common expected AEs linked to biologic (b) DMARDs in paediatric patients (pts) with juvenile idiopathic arthritis (JIA). Blood concentrations achieved with bDMARDs vary greatly between individual pts. It is not known if higher abatacept (ABA) exposure is linked to higher infection risk in paediatric populations. Objectives To assess the relationship between the incidence of infection and SC (50–125 mg weekly) and IV (10 mg/kg monthly) ABA exposure in pts with polyarticular-course JIA (pJIA). Methods Data from the 4 month open-label periods of a Phase III SC ABA study (NCT01844518; weight-tiered ABA: 10– Results Baseline demographic and clinical characteristics were comparable in the SC and IV studies.1 2 Overall, 135/403 pts (33.5%) had ≥1 infection over 4 months: 77/219 (35.2%) with SC ABA and 58/184 (31.5%) with IV ABA. KM plots for pooled SC and IV ABA showed no statistically significant difference in infection probability across four quartiles of ABA Cminss (Fig A; p=0.2317; log-rank test), Cmaxss (p=0.5501) or Cavgss (p=0.3808). Consistent results were seen for individually studied SC and IV ABA Cminss (Fig B, C), Cmaxss and Cavgss (not shown). In addition, there was no difference in median ABA exposure measures by infection occurrence (yes/no) in pooled and separate SC and IV analyses. Conclusions In pts with pJIA who received SC or IV abatacept, higher relative abatacept exposure was not associated with a higher risk of infections for 4 months. References [1] Ruperto N, et al. Lancet2008;372:383–91. [2] Lovell D, et al. Arthritis Rheumatol2016;68(Suppl 10), abstract 948. Disclosure of Interest N. Ruperto Grant/research support from: Bristol-Myers Squibb, Roche, Janssen, Novartis, Pfizer, Sobi, Consultant for: AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, MedImmune, Novartis, Pfizer, R-Pharm, Roche, Sanofi, Servier, Takeda, Speakers bureau: AbbVie, Ablynx, Amgen, AstraZeneca, Baxalta Biosimilars, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli-Lilly, EMD Serono, Gilead Sciences, Janssen, MedImmune, Novartis, Pfizer, R-Pharm, Roche, Sanofi, Servier, Takeda, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, Lilly, Janssen, Ablynx, AbbVie, Bristol-Myers Squibb, EMD Serono, AstraZeneca, Speakers bureau: Genentech, Novartis, N. Tzaribachev: None declared, I. Louw Consultant for: Janssen, Pfizer, Roche, I. Calvo Grant/research support from: Novartis, Speakers bureau: AbbVie, Novartis, Roche, Sobi, G. Horneff Grant/research support from: AbbVie, Bristol-Myers Squibb, Chugai, Pfizer, Janssen/MSD, Novartis, Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Chugai, Pfizer, Janssen/MSD, Novartis, Roche, M. Henrickson: None declared, M. Rama: None declared, M. Fischbach: None declared, T. Miraval: None declared, M. Ally: None declared, X. Li Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, R. Wong Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Nys Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, B. Murthy Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, K. Lin Employee of: Cognigen Corporation, a SimulationsPlus company, J. Passarell Employee of: Cognigen Corporation, a SimulationsPlus company, A. Martini Consultant for: AbbVie, Biogen, Boehringer-Ingelheim, Bristol-Myers Squibb, EMD Serono, Janssen, Novartis, Pfizer, R-Pharm, D. Lovell Grant/research support from: National Institutes of Health, NIAMS, Consultant for: AstraZeneca, Bristol-Myers Squibb, AbbVie, Pfizer, Roche, Novartis, UCB, Forest Research Institute, Horizon, Johnson and Johnson, Biogen, Takeda, Genentech, GlaxoSmithKline, Boehringer Ingelheim, Celgene, Janssen, Speakers bureau: Genentech

Methods Retrospective medical record review of a cohort of patients with KD over a 10 year period. All patients who met diagnostic criteria of KD seen in our Institution between January of 1999 and January of 2009 were included. The patient population was segregated into two groups according to the presence or absence of coronary aneurisms (CA + and CA -). Days from symptom onset to diagnosis and days from symptom onset to infusion were recorded. Demographic, clinical, echocardiographic and laboratory variables were recorded and described as well. Descriptive statistics and Mann-Whitney Rank Sum Test for comparison of groups were applied. A p ≤ 0.05 was considered significant.