A nanoengineered topical transmucosal cisplatin delivery system induces anti-tumor response in animal models and patients with oral cancer.

Despite therapeutic advancements, oral cavity squamous cell carcinoma (OCSCC) remains a difficult disease to treat. Systemic platinum-based chemotherapy often leads to dose-limiting toxicity (DLT), affecting quality of life. PRV111 is a nanotechnology-based system for local delivery of cisplatin loaded chitosan particles, that penetrate tumor tissue and lymphatic channels while avoiding systemic circulation and toxicity. Here we evaluate PRV111 using animal models of oral cancer, followed by a clinical trial in patients with OCSCC. In vivo, PRV111 results in elevated cisplatin retention in tumors and negligible systemic levels, compared to the intravenous, intraperitoneal or intratumoral delivery. Furthermore, PRV111 produces robust anti-tumor responses in subcutaneous and orthotopic cancer models and results in complete regression of carcinogen-induced premalignant lesions. In a phase 1/2, open-label, single-arm trial (NCT03502148), primary endpoints of efficacy (≥30% tumor volume reduction) and safety (incidence of DLTs) of neoadjuvant PRV111 were reached, with 69% tumor reduction in ~7 days and over 87% response rate. Secondary endpoints (cisplatin biodistribution, loco-regional control, and technical success) were achieved. No DLTs or drug-related serious adverse events were reported. No locoregional recurrences were evident in 6 months. Integration of PRV111 with current standard of care may improve health outcomes and survival of patients with OCSCC.

An Incidence of Duplicated Princeps Pollicis and Radialis Indicis Arteries.

The princeps pollicis artery (PPA) is typically a direct branch off the deep palmar arterial arch. Identified is a 90-year-old female cadaver in which the right hand has a duplicated PPA and radialis indicis (RI) artery. These vessels originate from the superficial palmar arterial arch as variant vessels as well as from the deep palmar arterial arch. The superficial arch appears in its classic pattern, while the duplicate PPA and RI present at the radial aspect of the superficial arch in the volar first web space with clear communication to the superficial radial artery. There are many common surgical procedures that require precise knowledge of the first web space, such as Dupuytren's contracture release, trigger thumb release, and syndactyly release at the first web space. Further, percutaneous pinning of fractures at the base of the thumb may pose an inherent risk to the underlying vessels. Understanding these variations of hand vasculature is of clinical significance in disciplines such as orthopedic surgery, plastic surgery and vascular surgery.

Influence of Sampling Site and Fluid Flow on the Accuracy of Total Body Clearance Calculation.

Studies have showed that by assuming arteriovenous drug concentrations are homogenous after intravenous injection, the determination of total body clearance based on venous drug concentrations is often inaccurate. This study considers the use of a fluidic pharmacokinetic profile generator where 28 different profile types were generated corresponding to a physiological model with varying sampling sites, administration locations, and fluid flow rates. Clearance was calculated using established equations, commercial software, and recently proposed models. The results show large differences in clearance values calculated with published equations and commercial software relative to the actual value of clearance. Alterations in sampling site, administration location, and fluid flow rates each influence the extent of calculation errors. The data show that a significant drug concentration gradient exists within the central circulatory system. The results show that the best way to address this issue would be to inject the drug at a peripheral location to allow for sufficient mixing and then sample from a large vein. Extrapolating for missing data can also lead to large errors in clearance calculation; this can be addressed by collecting more samples early after IV bolus administration or by collecting data during steady state conditions for an IV infusion.

Development of a Nanoparticle-Embedded Chitosan Sponge for Topical and Local Administration of Chemotherapeutic Agents.

The following work describes the development of a novel noninvasive transmucosal drug delivery system, the chitosan sponge matrix (CSM). It is composed of cationic chitosan (CS) nanoparticles (NPs) that encapsulate cisplatin (CDDP) embedded within a polymeric mucoadhesive CS matrix. CSM is designed to swell up when exposed to moisture, facilitating release of the NPs via diffusion across the matrix. CSM is intended to be administered topically and locally to mucosal tissues, with its initial indication being oral cancer (OC). Currently, intravenous (IV) administered CDDP is the gold standard chemotherapeutic agent used in the treatment of OC. However, its clinical use has been limited by its renal and hemotoxicity profile. We aim to locally administer CDDP via encapsulation in CS NPs and deliver them directly to the oral cavity with CSM. It is hypothesized that such a delivery device will greatly reduce any systemic toxicity and increase antitumor efficacy. This paper describes the methods for developing CSM and maintaining the integrity of CDDP NPs embedded in the CSM.