Mechanisms and Barriers in Nanomedicine: Progress in the Field and Future Directions.

In recent years, steady progress has been made in synthesizing and characterizing engineered nanoparticles, resulting in several approved drugs and multiple promising candidates in clinical trials. Regulatory agencies such as the Food and Drug Administration and the European Medicines Agency released important guidance documents facilitating nanoparticle-based drug product development, particularly in the context of liposomes and lipid-based carriers. Even with the progress achieved, it is clear that many barriers must still be overcome to accelerate translation into the clinic. At the recent conference workshop "Mechanisms and Barriers in Nanomedicine" in May 2023 in Colorado, U.S.A., leading experts discussed the formulation, physiological, immunological, regulatory, clinical, and educational barriers. This position paper invites open, unrestricted, nonproprietary discussion among senior faculty, young investigators, and students to trigger ideas and concepts to move the field forward.

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.

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.