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Figures including: Supplemental Figure 1- Dose finding pharmacokinetics. Supplemental Figure 2- Dose finding tissue biodistribution. Supplemental Figure 3- body weight over time in a therapy study. Supplemental Figure 4- blood counts over time in a therapy study. Supplemental Figure 5- fusion protein binding to Ramos and Granta cell lines

Streptavidin (SA)-biotin pretargeted radioimmunotherapy (PRIT) that targets CD20 in non-Hodgkin lymphoma (NHL) exhibits remarkable efficacy in model systems, but SA immunogenicity and interference by endogenous biotin may complicate clinical translation of this approach. In this study, we engineered a bispecific fusion protein (FP) that evades the limitations imposed by this system. Briefly, one arm of the FP was an anti-human CD20 antibody (2H7), with the other arm of the FP an anti-chelated radiometal trap for a radiolabeled ligand (yttrium[Y]-DOTA) captured by a very high-affinity anti-Y-DOTA scFv antibody (C825). Head-to-head biodistribution experiments comparing SA-biotin and bispecific FP (2H7-Fc-C825) PRIT in murine subjects bearing human lymphoma xenografts demonstrated nearly identical tumor targeting by each modality at 24 hours. However, residual radioactivity in the blood and normal organs was consistently higher following administration of 1F5-SA compared with 2H7-Fc-C825. Consequently, tumor-to-normal tissue ratios of distribution were superior for 2H7-Fc-C825 (P < 0.0001). Therapy studies in subjects bearing either Ramos or Granta subcutaneous lymphomas demonstrated that 2H7-Fc-C825 PRIT is highly effective and significantly less myelosuppressive than 1F5-SA (P < 0.0001). All animals receiving optimal doses of 2H7-Fc-C825 followed by 90Y-DOTA were cured by 150 days, whereas the growth of tumors in control animals progressed rapidly with complete morbidity by 25 days. In addition to demonstrating reduced risk of immunogenicity and an absence of endogenous biotin interference, our findings offer a preclinical proof of concept for the preferred use of bispecific PRIT in future clinical trials, due to a slightly superior biodistribution profile, less myelosuppression, and superior efficacy. Cancer Res; 76(22); 6669–79. ©2016 AACR.

The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin–biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals. Cancer Res; 74(4); 1179–89. ©2013 AACR.

PDF - 156K, Supplementary Figure 1, demonstrating CD38 receptor surface stability. Supplementary Figure 2, demonstrating animal body weight following anti-CD38 pretargeted radioimmunotherapy. Supplemental methods describing fusion protein construction as well as endocytosis and trichloroacetic acid (TCA) precipitation assays.

Cholesteryl ester liquid crystals exhibit thermochromic properties related to the existence of a twisted nematic phase. When used in applications such as thermal mapping, a color change is often monitored by video cameras. Thus, quantitative methods to evaluate thermochromic behavior (e.g., blue-start, red-start, red-end, color play and bandwidth) from video analysis are desirable. However, obtaining quantitative color measurements from digital images remains a significant technical challenge, especially for highly reflective samples such as liquid crystals (for which ultraviolet–visible (UV–vis) reflectance spectroscopy is typically used). We developed a method to determine thermochromic properties from videos of liquid crystal cooling under polarized light microscopy. We relate observed color transitions to quantifiable changes in the cumulative color difference in the International Commission on Illumination (CIE) L*a*b* color space and validate this method with UV–vis reflectance spectroscopy. The measured thermochromic behavior and associated measurement uncertainties (coefficient of variations) were comparable to UV–vis reflectance measurements.

Analysis of the costs associated with emergency department (ED) visits after discharge for violent injury could highlight subgroups for the development of cost-effective interventions to support healing and prevent treatment failures in violently injured patients.A retrospective cohort review was conducted of all patients with return ED visits within 90 days of discharge after treatment for a violent injury occurring between July 1, 2016, and June 30, 2018. Hospital costs were calculated for each incidence and analyzed against demographic and injury type variables to identify trends.218 return ED visits were identified. Hospital costs showed a high frequency of low-cost visits. For more complex visits, distinct cost patterns were observed for Black and LatinX males compared to White males as a function of age.Analysis of hospital cost per visit identified trends among different subgroups. Underlying etiologies presumably vary between groups, but hypothesis-driven further investigation and needs assessment is required. Understanding the driving forces behind these cost trends may aid in developing effective interventions.

The efficacy of paclitaxel (PTX) is limited due to its poor solubility, poor bioavailability, and acquired drug resistance mechanisms. Designing paclitaxel prodrugs can improve its anticancer activity and enable formulation of nanoparticles. Overall, the aim of this work is to improve the potency of paclitaxel with prodrug synthesis, nanoparticle formation, and synergistic formulation with lapatinib. Specifically, we improve potency of paclitaxel by conjugating it to &alpha, tocopherol (vitamin E) to produce a hydrophobic prodrug (Pro), this increase in potency is indicated by the 8-fold decrease in half maximal inhibitory concentration (IC50) concentration in ovarian cancer cell line, OVCA-432, used as a model system. The efficacy of the paclitaxel prodrug was further enhanced by encapsulation into pH-labile nanoparticles using Flash NanoPrecipitation (FNP), a rapid, polymer directed self-assembly method. There was an 1100-fold decrease in IC50 concentration upon formulating the prodrug into nanoparticles. Notably, the prodrug formulations were 5-fold more potent than paclitaxel nanoparticles. Finally, the cytotoxic effects were further enhanced by co-encapsulating the prodrug with lapatinib (LAP). Formulating the drug combination resulted in synergistic interactions as indicated by the combination index (CI) of 0.51. Overall, these results demonstrate this prodrug combined with nanoparticle formulation and combination therapy is a promising approach for enhancing paclitaxel potency.

Taxol, a formulation of paclitaxel (PTX), is one of the most widely used anticancer drugs, particularly for treating recurring ovarian carcinomas following surgery. Clinically, PTX is used in combination with other drugs such as lapatinib (LAP) to increase treatment efficacy. Delivering drug combinations with nanoparticles has the potential to improve chemotherapy outcomes. In this study, we use Flash NanoPrecipitation, a rapid, scalable process to encapsulate weakly hydrophobic drugs (logP &lt, 6) PTX and LAP into polymer nanoparticles with a coordination complex of tannic acid and iron formed during the mixing process. We determine the formulation parameters required to achieve uniform nanoparticles and evaluate the drug release in vitro. The size of the resulting nanoparticles was stable at pH 7.4, facilitating sustained drug release via first-order Fickian diffusion. Encapsulating either PTX or LAP into nanoparticles increases drug potency (as indicated by the decrease in IC-50 concentration), we observe a 1500-fold increase in PTX potency and a six-fold increase in LAP potency. When PTX and LAP are co-loaded in the same nanoparticle, they have a synergistic effect that is greater than treating with two single-drug-loaded nanoparticles as the combination index is 0.23 compared to 0.40, respectively.

Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m2 PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m2 IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m2 twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL.

Flash NanoPrecipitation (FNP) is a rapid method for encapsulating hydrophobic materials in polymer nanoparticles with high loading capacity. Encapsulating biologics such as proteins remains a challenge due to their low hydrophobicity (logP &lt, 6) and current methods require multiple processing steps. In this work, we report rapid, single-step protein encapsulation via FNP using bovine serum albumin (BSA) as a model protein. Nanoparticle formation involves complexation and precipitation of protein with tannic acid and stabilization with a cationic polyelectrolyte. Nanoparticle self-assembly is driven by hydrogen bonding and electrostatic interactions. Using this approach, high encapsulation efficiency (up to ~80%) of protein can be achieved. The resulting nanoparticles are stable at physiological pH and ionic strength. Overall, FNP is a rapid, efficient platform for encapsulating proteins for various applications.

Chitosan-based nanoparticles are promising materials for potential biomedical applications. We used Flash NanoPrecipitation as a rapid, scalable, single-step method to achieve self-assembly of crosslinked chitosan nanoparticles. Self-assembly was driven by electrostatic interactions, hydrogen bonding, and hydrophobic interactions, tannic acid served to precipitate chitosan to seed nanoparticle formation and crosslink the chitosan to stabilize the resulting particles. The size of the nanoparticles can be tuned by varying formulation parameters including the total solids concentration and block copolymer to core mass ratio. We demonstrated that hydrophobic moieties can be incorporated into the nanoparticle using a lipophilic fluorescent dye as a model system.

Advances in polymer colloid synthesis have enabled significant progress in nanomedicine. Focusing on polymer nanoparticles for drug delivery applications, this chapter provides an overview of material selection, processing, physiochemical property considerations, regulatory aspects, and emerging applications. Moving forward, the interface of polymer colloids and biological surfaces is promising for enhancing fundamental understanding as well as in vivo performance and ultimate therapeutic translation.