Intratumoral Injection of Large Surface Area Microparticle Taxanes in Carcinomas Increases Immune Effector Cell Concentrations, Checkpoint Expression, and Synergy with Checkpoint Inhibitors: A Review of Preclinical and Clinical Studies.

This review summarizes development of large surface area microparticle paclitaxel (LSAM-PTX) and docetaxel (LSAM-DTX) for local treatment of primary carcinomas with emphasis on immunomodulation. Intratumoral (IT) delivery of LSAM-PTX and LSAM-DTX provides continuous, therapeutic drug levels for several weeks. Preclinical studies and clinical trials reported a reduction in tumor volume (TV) and immunomodulation in primary tumor and peripheral blood with increases in innate and adaptive immune cells and decreases in suppressor cells.

Intratumoral Treatment of Melanoma Tumors with Large Surface Area Microparticle Paclitaxel and Synergy with Immune Checkpoint Inhibition.

The effects of intratumoral (IT) large surface area microparticle paclitaxel (LSAM-PTX) alone and in combination with systemic administration of the programmed cell death protein antibody (anti-mPD-1) were evaluated in a syngeneic murine model of melanoma. Groups of mice with subcutaneously implanted Clone M3 (Cloudman S91) tumors were treated with single and combination therapies. Tumor volume (TV) measurements, body weights, and clinical observations were followed in-life.

Response of Locally Advanced Pancreatic Cancer to Intratumoral Injection of Large Surface Area Microparticle Paclitaxel: Initial Report of Safety and Clinical Outcome.

Objectives: Large surface area microparticle paclitaxel (LSAM-PTX) provides an intratumoral (IT) chemotherapeutic depot. Safety, tolerability, and tumor response to IT LSAM-PTX delivered by endoscopic ultrasound-fine needle injection were evaluated in subjects with unresectable locally advanced pancreatic cancer (LAPC).

Methods: Ten subjects treated in a dose escalation phase and 22 additional subjects receiving 2 injections, 4 weeks apart, of 15 mg/mL LSAM-PTX were followed for 12 months.

Early phase trial of intracystic injection of large surface area microparticle paclitaxel for treatment of mucinous pancreatic cysts.

Mucinous pancreatic cystic lesions (PCLs) have the potential for malignant transformation, for which the only accepted curative modality is surgery. A novel intracystic therapy with large surface area microparticle paclitaxel (LSAM-PTX) may treat PCLs without local or systemic toxicities. Safety and preliminary efficacy of LSAM-PTX for the treatment of PCLs administered by endoscopic ultrasound-guided fine-needle injection (EUS-FNI) was evaluated.

Local administration of large surface area microparticle docetaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects: preclinical and clinical studies.

This report describes local administration of large surface area microparticle docetaxel (LSAM-DTX: ~ 3.5- to 7.5-µm-sized particles with high relative surface area) in preclinical oncology models and in a clinical trial in urothelial carcinoma.

Phase 1/2 Trial Results of a Large Surface Area Microparticle Docetaxel for the Treatment of High-Risk Nonmuscle-Invasive Bladder Cancer.

Purpose: We investigated the safety, preliminary efficacy, and immune effects of large surface area microparticle docetaxel (LSAM-DTX) administered by direct injection after transurethral resection of bladder tumor (TURBT), and by intravesical instillation in high-risk nonmuscle-invasive bladder cancer.

Materials And Methods: The trial followed an open-label 3+3 dose escalation with additional enrollment at the high dose. After TURBT, subjects received direct injection LSAM-DTX into the resection site and intravesical LSAM-DTX, followed by 6-week induction and 3-week maintenance intravesical LSAM-DTX courses.

Submicron particle docetaxel intratumoral injection in combination with anti-mCTLA-4 into 4T1-Luc orthotopic implants reduces primary tumor and metastatic pulmonary lesions.

We describe here characterization of the response of local and metastatic disease and immunomodulation following intratumoral (IT) injection of submicron particle docetaxel (SPD) administered alone or in combination with systemic antibody anti-mCTLA-4 (anti-mCTLA-4) in the metastatic 4T1-Luc2-1A4 (4T1) murine breast cancer model. In-life assessments of treatment tolerance, tumor volume (TV), and metastasis were performed (n = 10 animals/group). At study end, immune cell populations in tumor-site tissues and peripheral blood were analyzed using flow cytometry.

Countermeasure and therapeutic: A(1-7) to treat acute respiratory distress syndrome due to COVID-19 infection.

In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease.

Local administration of submicron particle paclitaxel to solid carcinomas induces direct cytotoxicity and immune-mediated tumoricidal effects without local or systemic toxicity: preclinical and clinical studies.

This report describes local administration of submicron particle paclitaxel (SPP) (NanoPac®: ~ 800-nm-sized particles with high relative surface area with each particle containing ~ 2 billion molecules of paclitaxel) in preclinical models and clinical trials evaluating treatment of carcinomas. Paclitaxel is active in the treatment of epithelial solid tumors including ovarian, peritoneal, pancreatic, breast, esophageal, prostate, and non-small cell lung cancer. SPP has been delivered directly to solid tumors, where the particles are retained and continuously release the drug, exposing primary tumors to high, therapeutic levels of paclitaxel for several weeks.

Phase II study of intraperitoneal submicron particle paclitaxel (SPP) plus IV carboplatin and paclitaxel in patients with epithelial ovarian cancersurgery.

Submicron particles (~800 nm) of paclitaxel (SPP) contain 1-2 billion molecules of pure drug that release tumoricidal levels of paclitaxel over many weeks. This study compared two dose-levels of SPP instilled into the peritoneal cavity (IP) in 200 ml of saline post-cytoreductive surgery. Eligible patients with primary (n = 6) or recurrent (n = 4) epithelial ovarian cancer who underwent complete cytoreductive surgery were enrolled to receive a single instillation of IP SPP followed by standard IV carboplatin and paclitaxel.

Intratumoral submicron particle docetaxel inhibits syngeneic Renca renal cancer growth and increases CD4+, CD8+, and Treg levels in peripheral blood.

Administration of chemotherapeutics as direct injections into tumors offers increased anti-tumor activity and reduced systemic toxicity. In this study, the Renca syngeneic murine xenograft model of renal cancer was used to evaluate the effects of intratumoral (IT) submicron particle docetaxel (NanoDoce®) on tumor growth and immunomodulation. Tumor volume (TV) was compared to controls, including intravenous (IV) chemotherapy.

Inhaled Submicron Particle Paclitaxel (NanoPac) Induces Tumor Regression and Immune Cell Infiltration in an Orthotopic Athymic Nude Rat Model of Non-Small Cell Lung Cancer.

This study evaluated the antineoplastic and immunostimulatory effects of inhaled (IH) submicron particle paclitaxel (NanoPac) in an orthotopic non-small cell lung cancer rodent model. Male nude rats were whole body irradiated, intratracheally instilled with Calu-3 cancer cells and divided into six treatment arms ( = 20 each): no treatment (Group 1); intravenous nab-paclitaxel at 5.0 mg/kg once weekly for 3 weeks (Group 2); IH NanoPac at 0.

Local Injection of Submicron Particle Docetaxel is Associated with Tumor Eradication, Reduced Systemic Toxicity and an Immunologic Response in Uro-Oncologic Xenografts.

Intratumoral (IT) administration of submicron particle docetaxel (NanoDoce, NanOlogy LLC, Fort Worth, TX, USA) and its efficacy against genitourinary-oncologic xenografts in rats and mice, xenograft-site docetaxel concentrations and immune-cell infiltration were studied. IT-NanoDoce, IV-docetaxel and IT-vehicle were administered to clear cell renal carcinoma (786-O: rats), transitional cell bladder carcinoma (UM-UC-3: mice) and prostate carcinoma (PC-3: mice). Treatments were given every 7 days with 1, 2, or 3 doses administered.

Pharmacokinetic Profile of Inhaled Submicron Particle Paclitaxel (NanoPac) in a Rodent Model.

Background: Inhaled chemotherapeutics may enhance pulmonary drug exposure to malignant lesions in the lung without substantially contributing to systemic toxicities. The pharmacokinetic profile of inhaled submicron particle paclitaxel (NanoPac) in healthy rodent plasma and lung tissue is evaluated here to determine administration proof-of-principle.

Methods: Healthy male Sprague Dawley rats received paclitaxel in one of three arms: intravenous nab-paclitaxel at 2.

Development of a guinea pig cutaneous radiation injury model using low penetrating X-rays.

Purpose: A guinea pig skin model was developed to determine the dose-dependent response to soft X-ray radiation into the dermis.

Materials And Methods: X-ray exposure (50 kVp) was defined to a 4.0 × 4.

Rapid reperitonealization and wound healing in a preclinical model of abdominal trauma repair with a composite mesh.

Purpose: Peritoneal tissue healing is characterized by the simultaneous repopulation of mesothelial cells and the formation of neoperitoneum. Despite the common use of mesh products for abdominal wall repair, there are few investigations of how these materials may impact the peritoneal healing process. Here, we utilized an animal model of abdominal trauma to specifically investigate the peritoneal healing process in conjunction with a composite (poliglecaprone 25-coated polypropylene) mesh.

NorLeu-Angiotensin (1-7) [DSC127] as a Therapy for the Healing of Diabetic Foot Ulcers.

Diabetes is a disorder that is well known to delay wound repair resulting in the formation of colonized chronic wounds. Over their lifetime, diabetic patients have a 25% incidence of foot ulcers (DFUs), which contribute to increased risk of morbidity, including osteomyelitis and amputations, and increased burden to the healthcare system. The only active product approved for the treatment of diabetic ulcers, Regranex, is not widely used due to minimal proven efficacy and recent warnings added to the Instructions for Use.

Effect of combined radiation injury on cell death and inflammation in skin.

In the event of a nuclear disaster, the individuals proximal to the source of radiation will be exposed to combined radiation injury. As irradiation delays cutaneous repair, the purpose of this study was to elucidate the effect of combined radiation and burn injury (CRBI) on apoptosis and inflammation at the site of skin injury. Male C57Bl/6 mice were exposed to no injury, thermal injury only, radiation only (1 and 6 Gy) and CRBI (1 and 6 Gy) and euthanized at various times after for skin collection.

Angiotensin 1 - 7 stimulation of platelet recovery.

Introduction: Thrombocytopenia is an abnormally low number of platelets in the blood resulting from either too few platelets being produced or existing platelets being destroyed. Severe thrombocytopenia leads to excessive bleeding and can be the result of numerous medical conditions or a side effect of medications or treatments. Although platelet transfusions are typically administered to correct thrombocytopenia, transfusions represent a temporary and unsustainable solution.

Contribution of the Local RAS to Hematopoietic Function: A Novel Therapeutic Target.

The renin-angiotensin system (RAS) has long been a known endocrine system that is involved in regulation of blood pressure and fluid balance. Over the last two decades, evidence has accrued that shows that there are local RAS that can affect cellular activity, tissue injury, and tissue regeneration. There are locally active ligand peptides, mediators, receptors, and signaling pathways of the RAS in the bone marrow (BM).

Angiotensin-(1-7) synergizes with colony-stimulating factors in hematopoietic recovery.

Purpose: Angiotensin (1-7) [A(1-7)] is a bioactive peptide of the renin angiotensin system that stimulates the number of bone marrow progenitors and hematopoietic recovery after myelosuppression. We evaluated the combination of A(1-7) with colony-stimulating factors, Neupogen and Epogen, on bone marrow progenitors and the recovery of circulating formed elements following chemotherapy.

Methods: Mice were injected with gemcitabine followed 2 days later with A(1-7).

Reduction of Leg Pain by Oxiplex Gel After Lumbar Discectomy in Patients With Predominant Leg Pain and Elevated Levels of Lower Back Pain: A Prospective, Randomized, Blinded, Multicenter Clinical Study.

Study Design: A prospective, randomized, blinded, multicenter clinical study.

Objective: To evaluate carboxymethylcellulose/polyethylene oxide gel (Oxiplex) in improving clinical outcomes in subjects having predominant leg pain and elevated low back pain undergoing first-time lumbar discectomy for disk herniation.

Summary Of Background Data: Clinical studies in the United States and Italy found that Oxiplex reduced leg pain after decompression surgery.

Pharmacodynamic stimulation of thrombogenesis by angiotensin (1-7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy.

Purpose: This randomized, double-blind, placebo-controlled Phase 2 study evaluated safety and efficacy of A(1-7) for reduction in Grade 3-4 thrombocytopenia in patients receiving myelosuppressive chemotherapy. Pharmacodynamic activity of A(1-7) in platelet production and retention of scheduled dose intensity were also determined.

Methods: Thirty-four patients with ovarian, Fallopian tube, or peritoneal carcinoma receiving gemcitabine and carboplatin or cisplatin were evaluated.

Effects of combined radiation and burn injury on the renin-angiotensin system.

The renin-angiotensin system (RAS) plays an important role in wound repair; however, little is known pertaining to RAS expression in response to thermal injury and the combination of radiation plus burn injury (CRBI). The purpose of this study was to test the hypothesis that thermal injury modifies expression of RAS components and CRBI delayed this up-regulation of RAS. Skin from uninjured mice was compared with mice receiving local thermal injury or CRBI (injury site).