Reducing off-target drug accumulation by exploiting a type-III interferon response.

Nanomedicines have been touted as the future of cancer therapy for decades. However, the field of tumor-targeted nanomedicine has failed to significantly advance toward becoming the primary choice for cancer intervention. One of the largest obstacles that has yet to be overcome is off-target accumulation of the nanoparticles. We propose a novel approach to tumor delivery by focusing on decreasing off-target accumulation of nanomedicines rather than directly increasing tumor delivery. Acknowledging a poorly understood "refractory" response to intravenously injected gene therapy vectors observed in ours and other studies, we hypothesize that virus-like particles (lipoplexes) can be utilized to initiate an anti-viral innate immune response that limits off-target accumulation of subsequently administered nanoparticles. Indeed, our results show a significant reduction in the deposition of both dextran and Doxil® in major organs with a concurrent increase in plasma and tumor accumulation when injection occurred 24 h after a lipoplex injection. Furthermore, our data showing that the direct injection of interferon lambda (IFN-λ) is capable of eliciting this response demonstrates a central role for this type III interferon in limiting accumulation in non-tumor tissues.

Cefazolin vs Second-line Antibiotics for Surgical Site Infection Prevention After Total Joint Arthroplasty Among Patients With a Beta-lactam Allergy.

Background: Cefazolin is a first-line agent for prevention of surgical site infections (SSIs) after total joint arthroplasty. Patients labeled allergic to beta-lactam antibiotics frequently receive clindamycin or vancomycin perioperatively due to the perceived risk of a hypersensitivity reaction after exposure to cefazolin. Methods: This single-system retrospective review included patients labeled allergic to penicillin or cephalosporin antibiotics who underwent a primary total hip and/or knee arthroplasty between January 2020 and July 2021. A detailed chart review was performed to compare the frequency of SSI within 90 days of surgery and interoperative hypersensitivity reactions (HSRs) between patients receiving cefazolin and patients receiving clindamycin and/or vancomycin. Results: A total of 1128 hip and/or knee arthroplasties from 1047 patients were included in the analysis (cefazolin n = 809, clindamycin/vancomycin n = 319). More patients in the clindamycin and/or vancomycin group had a history of cephalosporin allergy and allergic reactions with immediate symptoms. There were fewer SSIs in the cefazolin group compared with the clindamycin and/or vancomycin group (0.9% vs 3.8%; P < .001) including fewer prosthetic joint infections (0.1% vs 1.9%). The frequency of interoperative HSRs was not different between groups (cefazolin = 0.2% vs clindamycin/vancomycin = 1.3%; P = .06). Conclusions: The use of cefazolin as a perioperative antibiotic for infection prophylaxis in total joint arthroplasty in patients labeled beta-lactam allergic is associated with decreased postoperative SSI without an increase in interoperative HSR.