Engineering Low Volume Resuscitants for the Prehospital Care of Severe Hemorrhagic Shock.

Globally, traumatic injury is a leading cause of suffering and death. The ability to curtail damage and ensure survival after major injury requires a time-sensitive response balancing organ perfusion, blood loss, and portability, underscoring the need for novel therapies for the prehospital environment. Currently, there are few options available for damage control resuscitation (DCR) of trauma victims. We hypothesize that synthetic polymers, which are tunable, portable, and stable under austere conditions, can be developed as effective injectable therapies for trauma medicine. In this work, we design injectable polymers for use as low volume resuscitants (LVRs). Using RAFT polymerization, we evaluate the effect of polymer size, architecture, and chemical composition upon both blood coagulation and resuscitation in a rat hemorrhagic shock model. Our therapy is evaluated against a clinically used colloid resuscitant, Hextend. We demonstrate that a radiant star poly(glycerol monomethacrylate) polymer did not interfere with coagulation while successfully correcting metabolic deficit and resuscitating animals from hemorrhagic shock to the desired mean arterial pressure range for DCR - correcting a 60% total blood volume (TBV) loss when given at only 10% TBV. This highly portable and non-coagulopathic resuscitant has profound potential for application in trauma medicine.

Optimizing Inpatient Care for Lung Cancer Patients with Immune Checkpoint Inhibitor- Related Pneumonitis Using a Clinical Care Pathway Algorithm.

Purpose: Immune checkpoint inhibitor-related pneumonitis (ICI-P) is a condition associated with high mortality, necessitating prompt recognition and treatment initiation. This study aimed to assess the impact of implementing a clinical care pathway algorithm on reducing the time to treatment for ICI-P. Methods: Patients with lung cancer and suspected ICI-P were enrolled, and a multi-modal intervention promoting algorithm use was implemented in two phases. Pre- and post-intervention analyses were conducted to evaluate the primary outcome of time from ICI-P diagnosis to treatment initiation. Results: Of the 82 patients admitted with suspected ICI-P, 73.17% were confirmed to have ICI-P, predominantly associated with non-small cell lung cancer (91.67%) and stage IV disease (95%). Pembrolizumab was the most commonly used immune checkpoint inhibitor (55%). The mean times to treatment were 2.37 days in the pre-intervention phase and, 3.07 days (p=0.46), and 1.27 days (p=0.40) in the post-intervention phases 1 and 2, respectively. Utilization of the immunotoxicity order set significantly increased from 0% to 27.27% (p = 0.04) after phase 2. While there were no significant changes in ICU admissions or inpatient mortality, outpatient pulmonology follow-ups increased statistically significantly, demonstrating enhanced continuity of care. The overall mortality for patients with ICI-P was 22%, underscoring the urgency of optimizing management strategies. Notably, all patients discharged on high-dose corticosteroids received appropriate gastrointestinal prophylaxis and prophylaxis against Pneumocystis jirovecii pneumonia infections at the end of phase 2. Conclusion: Implementing a clinical care pathway algorithm for ICI-P management standardizes care practices and enhances patient outcomes, underscoring the importance of structured approaches.

Treatment patterns and outcomes of high-grade immune checkpoint inhibitor-related pneumonitis in an oncology hospitalist service.

PURPOSE: Immune checkpoint inhibitors (ICI) have become standard of care for some types of lung cancer. Along with expanding usage comes the emergence of immune-related adverse events (irAEs), including ICI-related pneumonitis (ICI-P). Treatment guidelines for managing irAEs have been developed; however, how clinicians manage irAEs in the real-world setting is less well known. We aimed to describe the outcomes and care patterns of grade ≥ 3 ICI-P in an onco-hospitalist service. PATIENTS AND METHODS: We included patients with lung cancer treated with ICI who were admitted to an oncology hospitalist service with a suspicion of ICI-P. We described the hospitalization characteristics, treatment patterns, discharge practices, and clinical outcomes of patients with confirmed ICI-P. The primary outcome was time to start treatment for ICI-P. RESULTS: Among 49 patients admitted with a suspicion of ICI-P, 31 patients were confirmed to have ICI-P and subsequently received ICI-P directed treatment. Pulmonology was consulted in 97% of patients. Median time to start treatment for ICI-P was 1 day (IQR 0-3.5 days). All 31 patients received corticosteroids. Inpatient mortality was 32%. Majority of patients discharged with steroids were prescribed prophylaxis for gastritis and opportunistic infections. Thirty-eight percent of patients were seen by pulmonology and 86% were seen by the oncology team post-discharge. CONCLUSION: Our study confirms prior findings of high mortality among patients with high-grade ICI-P. Early diagnosis and treatment are key to improving clinical outcomes. Understanding the care patterns and adherence to treatment guidelines of clinicians caring for this patient population may help identify ways to further standardize management practices and improve patient outcomes.

In situ chemically crosslinked injectable hydrogels for the subcutaneous delivery of trastuzumab to treat breast cancer.

Recently, novel approaches for the delivery of therapeutic antibodies have attracted much attention, especially sustained release formulations. However, sustained release formulations capable of carrying a high antibody load remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide-modified γ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4-arm PEG-SH) was developed for the subcutaneous delivery of trastuzumab. γ-PGA-MA and 4-arm PEG-SH formed a hydrogel through thiol-maleimide reactions, which had shear-thinning properties and reversible rheological behaviors. Moreover, a high content of trastuzumab (>100 mg/mL) could be loaded into this hydrogel, and trastuzumab demonstrated a sustained release over several weeks through electrostatic attraction. In addition, trastuzumab released from the hydrogel had adequate stability in terms of its structural integrity, binding bioactivity, and antiproliferative effect on BT-474 cells. Pharmacokinetic studies demonstrated that trastuzumab-loaded hydrogel (Her-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, and 10 mg/mL trastuzumab) and trastuzumab/Zn-loaded hydrogel (Her/Zn-hydrogel-10, composed of 1.5% γ-PGA-MA, 1.5% 4-arm PEG-SH, 5 mM ZnCl2, and 10 mg/mL trastuzumab) could lower the maximum plasma concentration (Cmax) than the trastuzumab solution. Furthermore, Her/Zn-hydrogel-10 was better able to release trastuzumab in a controlled manner, which was ascribed to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In a BT-474 xenograft tumor model, Her-hydrogel-10 had a similar tumor growth-inhibitory effect as that of the trastuzumab solution. By contrast, Her/Zn-hydrogel-10 exhibited a superior tumor growth-inhibitory capability due to the functionality of Zn. This study demonstrated that this hydrogel has potential as a carrier for the local and systemic delivery of proteins and antibodies. STATEMENT OF SIGNIFICANCE: Recently, novel sustained-release formulations of therapeutic antibodies have attracted much attention. However, these formulations should be able to carry a high antibody load owing to the required high dose, and these formulations remain a challenge for practical use. In this study, a novel injectable chemically cross-linked hydrogel was developed for the subcutaneous delivery of trastuzumab. This novel hydrogel possessed ideal characteristics of loading high content of trastuzumab (>100 mg/mL), sustained release of trastuzumab over several weeks, and maintaining adequate stability of trastuzumab. In vivo studies demonstrated that a trastuzumab-loaded hydrogel possessed the ability of controlled release of trastuzumab and maintained antitumor efficacy same as that of trastuzumab. These results implied that a γ-PGA-MA and 4-arm PEG-SH-based hydrogel has great potential in serving as a carrier for the local or systemic delivery of therapeutic proteins or antibodies.

Impact of a pharmacy-driven transitions-of-care program on postdischarge healthcare utilization at a national comprehensive cancer center.

PURPOSE: Results of a study comparing readmission rates and medication adherence measures before and after implementation of a pharmacy-led transitions-of-care (TOC) program are reported. METHODS: A quasi-experimental case-control study was conducted to assess the impact of a TOC program including medication history-taking and reconciliation services, inpatient and discharge education, and 72-hour and 30-day postdischarge phone follow-up. Hospital and emergency room (ER) readmission rates were compared in cohorts of oncology patients admitted to a large teaching hospital during specified periods before TOC program implementation (the standard-of-care [SOC] group) or after program implementation (the TOC group). The primary outcome was unplanned hospital or ER readmission within 30 days after initial discharge. The secondary endpoint was first-fill medication adherence. Benefits associated with specific TOC interventions were assessed in subgroup analyses. RESULTS: After propensity score matching, both study groups consisted of 323 patients. The SOC group had 76 patients (23.5%) and the TOC group had 74 patients (22.9%) who were readmitted to the hospital or ER within 30 days, with a significant reduction in hospital readmissions in 1 subgroup of TOC patients versus SOC controls (absolute difference, -7.6%; p = 0.0159). CONCLUSION: While there were no significant overall differences in readmission rates between the TOC and SOC groups, hospital readmissions were reduced in the subgroup of TOC patients who received both medication history-taking and reconciliation services and phone follow-up as TOC interventions.

A New Approach to Deliver Anti-cancer Nanodrugs with Reduced Off-target Toxicities and Improved Efficiency by Temporarily Blunting the Reticuloendothelial System with Intralipid.

We have developed a new strategy to temporarily blunt the reticuloendothelial system uptake of nanodrugs, a major challenge for nanodrug delivery and causing off-target toxicities, using an FDA approved nutrition supplement, Intralipid. We have tested our methodology in rats using an experimental platinum-containing anti-cancer nanodrug and three FDA approved nanodrugs, Abraxane, Marqibo, and Onivyde, to determine their toxicities in liver, spleen, and kidney, with and without the addition of Intralipid. Our method illustrates its potentials to deliver nanodrugs with an increase in the bioavailability and a decrease in toxicities. Our study shows that Intralipid treatment exhibits no harmful effect on tumor growing and no negative effect on the anti-tumor efficacy of the platinum-containing nanodrug, as well as animal survival rate in a HT-29 xenograft mouse model. Our methodology could also be a valuable complement/supplement to the "stealth" strategies. Our approach is a general one applicable to any approved and in-development nanodrugs without additional modification of the nanodrugs, thus facilitating its translation to clinical settings.

Update of Targeted Therapy-Induced Hypertension: Basics for Non-Oncology Providers.

Over the past several years, cancer treatments have expanded from usual chemotherapy standards with introduction of newer targeted therapies. As with chemotherapy, the targeted therapies also have unique side effects affecting various organ systems producing toxicities, such as cardiac and renal. This manuscript focuses on hypertension induced by vascular endothelial growth factor (VEGF) inhibitors and tyrosine kinase inhibitors (TKI). Hypertension due to these cancer therapies is important because these agents are now frequently used in common cancers. In addition, patients with cancer may not be treated in a comprehensive cancer center with experts available to manage the cancer and other side effects either from the malignancy or treatment of the malignancy. Especially in rural areas, patients are often managed or co-managed by a primary care provider with input from an oncologist that may not be nearby. Our aim is to provide an overview of the latest Federal Drug Administration (FDA) approved VEGF inhibitors and TKI's causing hypertension so that others managing patients on these treatments may easily recognize hypertension attributable to these agents and feel comfortable and confident in providing appropriate management and treatment of this side effect. This update includes characteristics, such as mechanism of action, metabolism and route of administration, and management and treatment of hypertension with aspects such as the timing, duration and monitoring of these agents. In addition, an algorithm for monitoring and treating hypertension before, during and after treatment with these therapies is included. It is imperative for patients to have hypertension promptly treated to prevent complications so they may continue with these agents with the least interruption or discontinuation of treatment, ensuring the best benefit available in their cancer trajectory.

Interleukin-4 receptor-targeted liposomal doxorubicin as a model for enhancing cellular uptake and antitumor efficacy in murine colorectal cancer.

Our previous studies showed that colorectal tumor has high interleukin-4 receptor α (IL-4Rα) expression, whereas adjacent normal tissue has low or no IL-4Rα expression. We also observed that human atherosclerotic plaque-specific peptide-1 (AP1) can specifically target to IL-4Rα. In this study, we investigated the therapeutic efficacy and systemic toxicity of AP1-conjuagted liposomal doxorubicin. AP1 bound more strongly to and was more efficiently internalized into IL-4Rα-overexpressing CT26 cells than CT26 control cells. Selective cytotoxicity experiment revealed that AP1-conjugated liposomal doxorubicin preferentially killed IL-4Rα-overexpressing CT26 cells. AP1-conjugated liposomal doxorubicin administered intravenously into mice produced significant inhibition of tumor growth and showed decreased cardiotoxicity of doxorubicin. These results indicated that AP1-conjugated liposomal doxorubicin has a potent and selective anticancer potential against IL-4Rα-overexpressing colorectal cancer cells, thus providing a model for targeted anticancer therapy.

A new approach to reduce toxicities and to improve bioavailabilities of platinum-containing anti-cancer nanodrugs.

Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2-diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively.

Enhanced delivery of liposomes to lung tumor through targeting interleukin-4 receptor on both tumor cells and tumor endothelial cells.

A growing body of evidence suggests that pathological lesions express tissue-specific molecular targets or biomarkers within the tissue. Interleukin-4 receptor (IL-4R) is overexpressed in many types of cancer cells, including lung cancer. Here we investigated the properties of IL-4R-binding peptide-1 (IL4RPep-1), a CRKRLDRNC peptide, and its ability to target the delivery of liposomes to lung tumor. IL4RPep-1 preferentially bound to H226 lung tumor cells which express higher levers of IL-4R compared to H460 lung tumor cells which express less IL-4R. Mutational analysis revealed that C1, R2, and R4 residues of IL4RPep-1 were the key binding determinants. IL4RPep-1-labeled liposomes containing doxorubicin were more efficiently internalized in H226 cells and effectively delivered doxorubicin into the cells compared to unlabeled liposomes. In vivo fluorescence imaging of nude mice subcutaneously xenotransplanted with H226 tumor cells indicated that IL4RPep-1-labeled liposomes accumulate more efficiently in the tumor and inhibit tumor growth more effectively compared to unlabeled liposomes. Interestingly, expression of IL-4R was high in vascular endothelial cells of tumor, while little was detected in vascular endothelial cells of control organs including the liver. IL-4R expression in cultured human vascular endothelial cells was also up-regulated when activated by a pro-inflammatory cytokine tumor necrosis factor-α. Moreover, the up-regulation of IL-4R expression was observed in primary human lung cancer tissues. These results indicate that IL-4R-targeting nanocarriers may be a useful strategy to enhance drug delivery through the recognition of IL-4R in both tumor cells and tumor endothelial cells.

Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control.

The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil(®), the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future.

A pharmacokinetics study of radiolabeled micelles of a poly(ethylene glycol)-block-poly(caprolactone) copolymer in a colon carcinoma-bearing mouse model.

A copolymer of poly(ethylene glycol)-b-poly(caprolactone) (PEG-PCL) was modified with a benzyl moiety and labeled with I-131. A micelle system, (131)I-benzyl-micelles, formed from (131)I-benzyl-PEG-PCL and PEG-PCL-PC, was created and used for in vitro characterization and in vivo evaluation. Administration of (131)I-benzyl-micelles to a colon carcinoma-bearing mouse model gives a 4.9-fold higher tumor-to-muscle ratio at 48 h post-injection than treatment with the unimer (131)I-benzyl-PEG-PCL. Scintigraphic imaging, biodistribution results and pharmacokinetical evaluation all demonstrated that (131)I-benzyl-micelles are a plausible radioactive surrogate for PEG-PCL copolymer micelles. Modifying the amphiphilic copolymer with a benzyl moiety and labeled it with iodine-131 should make possible the real-time and noninvasive evaluation of the pharmacokinetics of copolymer micelles in vivo.

Pharmacokinetic analysis of 111 in-labeled liposomal Doxorubicin in murine glioblastoma after blood-brain barrier disruption by focused ultrasound.

The goal of this study was to evaluate the pharmacokinetics of targeted and untargeted (111)In-doxorubicin liposomes after these have been intravenously administrated to tumor-bearing mice in the presence of blood-brain barrier disruption (BBB-D) induced by focused ultrasound (FUS). An intracranial brain tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells was developed in this study. (111)In-labeled human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (Lipo-Dox; AP-1 Lipo-Dox) were used as a microSPECT probe for radioactivity measurements in the GBM-bearing mice. Compared to the control tumors treated with an injection of (111)In-AP-1 Lipo-Dox or (111)In-Lipo-Dox, the animals receiving the drugs followed by FUS exhibited enhanced accumulation of the drug in the brain tumors (p<0.05). Combining sonication with drugs significantly increased the tumor-to-normal brain doxorubicin ratio of the target tumors compared to the control tumors. The tumor-to-normal brain ratio was highest after the injection of (111)In-AP-1 Lipo-Dox with sonication. The (111)In-liposomes micro-SPECT/CT should be able to provide important information about the optimum therapeutic window for the chemotherapy of brain tumors using sonication.

Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound.

BACKGROUND: High-dose tissue-specific delivery of therapeutic agents would be a valuable clinical strategy. We have previously shown that repeated transcranial focused ultrasound is able to increase the delivery of Evans blue significantly into brain tissue. The present study shows that repeated pulsed high-intensity focused ultrasound (HIFU) can be used to deliver high-dose atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes selectively to brain tumors. METHODS: Firefly luciferase (Fluc)-labeled human GBM8401 glioma cells were implanted into NOD-scid mice. AP-1-conjugated liposomal doxorubicin or liposomal doxorubicin alone was administered followed by pulsed HIFU and the doxorubicin concentration in the treated brains quantified by fluorometer. Growth of the labeled glioma cells was monitored through noninvasive bioluminescence imaging and finally the brain tissue was histologically examined after sacrifice. RESULTS: Compared with the control group, the animals treated with 5 mg/kg injections of AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin followed by repeated pulsed HIFU not only showed significantly enhanced accumulation of drug at the sonicated tumor site but also a significantly elevated tumor-to-normal brain drug ratio (P < 0.001). Combining repeated pulsed HIFU with AP-1 liposomal doxorubicin or untargeted liposomal doxorubicin has similar antitumor effects. CONCLUSION: This study demonstrates that targeted or untargeted liposomal doxorubicin, followed by repeated pulsed HIFU, is a promising high-dose chemotherapy method that allows the desired brain tumor region to be targeted specifically.

Focused ultrasound and interleukin-4 receptor-targeted liposomal doxorubicin for enhanced targeted drug delivery and antitumor effect in glioblastoma multiforme.

The clinical application of chemotherapy to brain tumors has been severely limited because the blood-brain barrier (BBB) often prevents therapeutic levels from being achieved. Here we show that pulsed HIFU and human atherosclerotic plaque-specific peptide-1 (AP-1)-conjugated liposomes containing doxorubicin (AP-1 Lipo-Dox) act synergistically in an experimental brain tumor model. We developed an intracranial brain-tumor model in NOD-scid mice using human brain glioblastoma multiforme (GBM) 8401 cells. Pulsed HIFU was used to transcranially disrupt the BBB in these mouse brains by delivering ultrasound waves in the presence of microbubbles. Prior to each sonication, AP-1 Lipo-Dox or unconjugated Lipo-Dox was administered intravenously, and the concentration in the brains was quantified by fluorometer. Compared to control animals treated with injections of AP-1 Lipo-Dox or unconjugated Lipo-Dox, animals receiving the drug followed by pulsed HIFU exhibited enhanced accumulation of the drug in tumor cells. Drug injection with sonication increased the tumor-to-normal brain doxorubicin ratio of the target tumors by about twofold compared with the control tumors. Moreover, the tumor-to-normal brain ratio was highest after the injection of AP-1 Lipo-Dox with sonication. Combining sonication with AP-1 Lipo-Dox also significantly inhibited tumor growth compared with chemotherapy alone. There was a modest but significant increase in the median survival time in mice treated with AP-1 Lipo-Dox followed by pulsed HIFU, compared to those treated with AP-1 Lipo-Dox without sonication. The use of AP-1-conjugated liposomes carrying cytotoxic agents followed by pulsed HIFU represents a feasible approach for enhanced targeted drug delivery in brain tumor therapies.

Failures in a proton pump inhibitor therapeutic substitution program: lessons learned.

The pathogenesis of patient dissatisfaction following involuntary therapeutic substitutions involving proton pump inhibitors (PPIs) is poorly understood. The aim of this study was to describe the patient population experiencing therapeutic failure and investigate whether failure was related to individual differences in response to the different PPIs. Treatment failures in a lansoprazole-rabeprazole therapeutic substitution program were compared to switch successes. A subgroup was randomized in a double-blind, double-dummy, crossover study to four 2-week periods of lansoprazole-rabeprazole-lansoprazole-rabeprazole or vice versa. Measures included overall rating of gastrointestinal reflux disease (GERD) symptoms for the past week as well as the frequency and distress scales of the GERD Symptom Assessment Scale. One hundred fifteen nonresponders were compared with 54 successful responders. Nonresponders consisted primarily of patients with GERD (74%, vs. 44% of responders; P = 0.005) who had undergone upper gastrointestinal endoscopy (50%, vs. 31% of responders; P = 0.02). Twelve patients completed the randomized treatment study. The interrater kappa coefficient for responder status was estimated to be 0.80 for lansoprazole and 0.21 for rabeprazole. The majority of PPI nonresponders had a clinical diagnosis of GERD and were receiving >/=40 mg of rabeprazole daily. This pilot study provides new insights into the design of subsequent studies of nonresponders in PPI therapeutic substitution programs.