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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. At end of study, tumor-site tissues were collected, measured, and processed for flow cytometry along with blood and lymph nodes. The combination of LSAM-PTX + anti-mPD-1 resulted in an antitumoral response, which produced a significant decrease in TV compared to control animals. TV decreases also occurred in the LSAM-PTX and anti-mPD-1 groups. Flow cytometry analysis found increases in granulocytes and M2 macrophages and decreases in dendritic cells (DC) and monocytic myeloid-derived suppressor cells (M-MDSC) in tumor-site tissues. Increases in granulocytes and decreases in CD4+ T cells, macrophages, and M1 macrophages were found in the blood of animals administered the combination treatment. Increases in natural killer (NK) cells were found in lymph node tissue in the combination treatment group. These findings suggest that IT LSAM-PTX may provide benefit in the local treatment of melanomas and may synergize with systemic anti-PD-1 therapy, leading to additional tumoricidal outcomes without added systemic toxicity.
Subject(s)
Immune Checkpoint Inhibitors , Melanoma , Mice , Animals , Immune Checkpoint Inhibitors/pharmacology , Melanoma/drug therapy , Paclitaxel/pharmacology , Cell Line, Tumor , Combined Modality Therapy , Tumor MicroenvironmentABSTRACT
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. Increased levels of checkpoint expression of immune cells occurred in clinical trials of high-risk non-muscle-invasive bladder cancer (LSAM-DTX) and unresectable localized pancreatic cancer (LSAM-PTX). TV reduction and increases in immune effector cells occurred following IT LSAM-DTX and IT LSAM-PTX together with anti-mCTLA-4 and anti-mPD-1, respectively. Synergistic benefits from combinatorial therapy in a 4T1-Luc breast cancer model included reduction of metastasis with IT LSAM-DTX + anti-mCTLA-4. IT LSAM-PTX and LSAM-DTX are tumoricidal, immune enhancing, and may improve solid tumor response to immune checkpoint inhibitors without additional systemic toxicity.
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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. Paclitaxel pharmacokinetics were evaluated, imaging at 3 and 6 months determined tumor response, and multiplex immunofluorescence was conducted to characterize local immune response. RESULTS: Most treatment-emergent adverse events were attributed to LAPC. Plasma paclitaxel levels were negligible. Eight subjects' tumors became resectable after IT LSAM-PTX, and 5 of 6 (83%) were resected with R0. Multiplex immunofluorescence of resected tumors demonstrated increased T cells, natural killer cells, and macrophages and decreased myeloid-derived suppressor cells. Six-month disease control rate was 94%, and median overall survival was 19.7 months in the 2-injection subjects. For nonresected and resected groups, overall survival times were 18.9 and 35.2 months, respectively. CONCLUSIONS: Neoadjuvant IT LSAM-PTX, in combination with SOC, was well tolerated and may provide benefits to LAPC patients, evidenced by enhanced immune response, improved disease control rate, restaging leading to surgery, and extended survival.
Subject(s)
Paclitaxel , Pancreatic Neoplasms , Humans , Injections, Intralesional , Neoadjuvant Therapy/methods , Pancreatic Hormones , Pancreatic Neoplasms/pathology , Pancreatic NeoplasmsABSTRACT
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. Reductions in tumor volumes were found following intratumoral (IT) injection of LSAM-DTX into human urologic carcinoma cell lines and syngeneic murine renal and breast cancer cell lines. Compared to IT injections of docetaxel solution typically administered intravenously, IT LSAM-DTX results in 40-fold more docetaxel retained within the tumor. The long residence time of LSAM-DTX within the tumor acts as a drug depot, allowing for continuous release of docetaxel, exposing tumor cells to high, therapeutic levels of chemotherapeutic for several weeks. Local LSAM-DTX results in tumoricidal effects at the site of deposition as well as in distant tumors, and IT LSAM-DTX in combination with immune checkpoint inhibitor therapy reduces or eliminates metastatic spread. Tumoricidal effects of local LSAM-DTX are accompanied by immunomodulation including increases in innate and adaptive immune cells in the tumor microenvironment and peripheral blood. Encouraging clinical results indicate that local administration of LSAM-DTX may provide therapeutic benefits for non-muscle invasive bladder cancer and muscle invasive bladder cancer patients; treatments were well-tolerated with few local and systemic adverse events and negligible systemic docetaxel exposure. Results of preclinical and clinical investigations summarized here indicate that local administration of LSAM-DTX may augment tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity.
Subject(s)
Antineoplastic Agents , Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Animals , Mice , Docetaxel , Urinary Bladder Neoplasms/drug therapy , Cell Line, Tumor , Tumor MicroenvironmentABSTRACT
Background and study aims 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. Patients and methods Ten subjects with confirmed PCLs (sizeâ>â1.5âcm) received intracystic LSAM-PTX via EUS-FNI at volumes equal to those aspirated from the cyst in sequential cohorts at 6, 10, and 15âmg/mL in a standard "3â+â3" dose-escalation protocol. The highest dose with acceptable safety and tolerability was taken into the confirmatory phase where nine additional subjects received two injections of LSAM-PTX 12 weeks apart. Subjects were followed for 6 months after initial LSAM-PTX treatment for endpoints including: adverse events (AEs), tolerability, pharmacokinetic analysis of systemic paclitaxel drug levels, and change in cyst volume. Results Nineteen subjects completed the study. No dose-limiting toxicities, treatment-related serious AEs, or clinically significant laboratory changes were reported. Systemic paclitaxel concentrations did not exceed 3.5âng/mL at any timepoint measured and fell below 1âng/mL by Week 2, supporting the lack of systemic toxicity. By Week 24 a cyst volume reduction (10-78â%) was seen in 70.6â% of subjects. Conclusions Intracystic injection of LSAM-PTX into mucinous PCLs resulted in no significant AEs, a lack of systemic absorption, and resulted in reduction of cyst volume over a 6 month period.
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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. Tumor recurrence was evaluated by cytology, cystoscopy, or biopsy. Pharmacokinetic analysis of blood and multiplex immunofluorescence of tumor microenvironment occurred pre- and post-LSAM-DTX. RESULTS: Nineteen subjects were enrolled, 14 with prior bacillus Calmette-Guérin exposure and 16 with ≥1 prior TURBT. Direct injection and intravesical LSAM-DTX were well tolerated. In the 3 lowest dose escalation cohorts the median recurrence-free survival was 5.4 months (10 patients, median followup 8.6 months). In the high-dose and expansion cohorts median recurrence-free survival was significantly increased (p <0.05, hazard ratio 0.29) to 12.2 months (9 patients, median followup 12.4 months). Systemic docetaxel exposure was negligible and increases in antitumor immune cells were found in the tumor microenvironment along with elevations in the PD-1, PD-L1 and CTLA-4 immune checkpoint inhibitor targets. CONCLUSIONS: Post-TURBT direct injection and intravesical LSAM-DTX were well tolerated and demonstrated clinical response for patients with high-risk nonmuscle-invasive bladder cancer. Favorable immune cell infiltration and checkpoint receptor increases following LSAM-DTX treatment warrants investigation alone as well as in combination with immune checkpoint inhibitor therapy.
Subject(s)
Urinary Bladder Neoplasms , Administration, Intravesical , BCG Vaccine/therapeutic use , Docetaxel/therapeutic use , Humans , Immune Checkpoint Inhibitors , Neoplasm Invasiveness/pathology , Neoplasm Recurrence, Local/pathology , Treatment Outcome , Tumor Microenvironment , Urinary Bladder Neoplasms/surgeryABSTRACT
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. Signs of distress typical of this aggressive tumor model occurred across all animals except for the combination treated which were asymptomatic and gained weight. TV at study end was significantly reduced in the combination group versus untreated [43% reduced (p < 0.05)] and vehicle controls [54% reduced (p < 0.0001)]. No evidence of thoracic metastasis was found in 40% of combination group animals and thoracic bioluminescence imaging (BLI) was reduced vs. untreated controls (p < 0.01). Significant elevations (p < 0.05) in CD4 + T, CD4 + helper T, Treg, and NKT cells were found in tumor and blood in SPD or combination treatment compared to controls or anti-mCTLA-4. Combination treatment increased tumor-associated CD8 + T cells (p < 0.01), peripheral B cells (p < 0.01), and tumor associated and circulating dendritic cells (DC) (p < 0.05). Tumor-associated NK cells were significantly increased in SPD ± anti-mCTLA-4 treatments (p < 0.01). Myeloid-derived suppressor cells (MDSC) were reduced in bloods in SPD ± anti-mCTLA-4 groups (p < 0.05). These data demonstrate that both SPD and anti-mCTLA-4 produce local anti-tumor effects as well as reductions in metastasis which are significantly enhanced when administered in combination.
Subject(s)
Antibodies, Monoclonal/pharmacology , CTLA-4 Antigen/antagonists & inhibitors , Docetaxel/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Lung Neoplasms/drug therapy , Lymphocytes, Tumor-Infiltrating/immunology , Mammary Neoplasms, Animal/drug therapy , Animals , Antibodies, Monoclonal/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , CTLA-4 Antigen/immunology , Combined Modality Therapy , Docetaxel/administration & dosage , Docetaxel/chemistry , Female , Injections, Intralesional , Killer Cells, Natural/immunology , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Lung Neoplasms/secondary , Mammary Neoplasms, Animal/immunology , Mammary Neoplasms, Animal/metabolism , Mammary Neoplasms, Animal/pathology , Mice , Mice, Inbred BALB C , Myeloid-Derived Suppressor Cells/immunology , Particle Size , T-Lymphocytes, Regulatory/immunology , Tumor BurdenABSTRACT
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. As a result, tumor cell death shifts from primarily apoptosis to both apoptosis and necroptosis. Direct local tumoricidal effects of paclitaxel, as well as stimulation of innate and adaptive immune responses, contribute to antineoplastic effects. Local administration of SPP may facilitate tumor response to systemically administered chemotherapy, targeted therapy, or immunotherapy without contributing to systemic toxicity. Results of preclinical and clinical investigations described here suggest that local administration of SPP achieves clinical benefit with negligible toxicity and may complement standard treatments for metastatic disease.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma , Lung Neoplasms , Carcinoma/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Immunotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Male , PaclitaxelABSTRACT
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. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).
Subject(s)
Angiotensin I/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/complications , Peptide Fragments/therapeutic use , Pneumonia, Viral/complications , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/virology , Angiotensin I/physiology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/mortality , Humans , Pandemics , Peptide Fragments/physiology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2ABSTRACT
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. Endpoints were PFS and evaluation of treatment emergent adverse events. Clinical response was determined by symptoms, physical exams, CT scans, and serum CA-125 measurements. Of the 24 subjects screened, 10 were enrolled and received treatment: seven patients received 100 mg/m2 and three received 200 mg/m2. Seven subjects completed the 12-month follow-up period. Six patients were evaluable due to one subject who had unevaluable scans throughout the follow-up period and was thus excluded from PFS determination. Upon completion of planned chemotherapy post-SPP instillation, the PFS at 6 months was 66% (4/6) and at 12-months 66% (4/6) using RECIST 1.1. One subject had a complete response at the end of IV treatment but died (unrelated to study treatment) before PFS evaluation. There was one case of incision dehiscence and one case of vaginal cuff leakage after surgery. This pilot study supports further evaluation of IP SPP to treat peritoneal carcinomas.
ABSTRACT
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. Flow cytometry of peripheral bloods and tumors was used to evaluate immune cell populations. Groups of animals were inoculated with a second Renca tumor at a site distant from the primary tumor. IT NanoDoce significantly reduced primary TV and reduced the growth rates of untreated secondary tumors. CD4+, CD8+ and Treg populations were increased in peripheral bloods from animals administered IT NanoDoce. Additional evaluation of the effect of IT NanoDoce on peripheral and local immune cell populations as well as the impact on sites of distant tumor growth are warranted.
Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Renal Cell/drug therapy , Docetaxel/administration & dosage , Kidney Neoplasms/drug therapy , Nanoparticles/administration & dosage , Animals , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Female , Kidney Neoplasms/blood , Kidney Neoplasms/immunology , Kidney Neoplasms/pathology , Mice, Inbred BALB C , T-Lymphocytes, Regulatory/drug effects , Tumor Burden/drug effectsABSTRACT
Background: 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. Methods: Male nude rats were whole body irradiated, intratracheally instilled with Calu-3 cancer cells and divided into six treatment arms (n = 20 each): no treatment (Group 1); intravenous nab-paclitaxel at 5.0 mg/kg once weekly for 3 weeks (Group 2); IH NanoPac at 0.5 or 1.0 mg/kg, once weekly for 4 weeks (Groups 3 and 4), or twice weekly for 4 weeks (Groups 5 and 6). Upon necropsy, left lungs were paraffin embedded, serially sectioned, and stained for histopathological examination. A subset was evaluated by immunohistochemistry (IHC), anti-pan cytokeratin staining AE1/AE3+ tumor cells and CD11b+ staining dendritic cells, natural killer lymphocytes, and macrophage immune cells (n = 2, Group 1; n = 3 each for Groups 2-6). BCL-6 staining identified B lymphocytes (n = 1 in Groups 1, 2, and 6). Results: All animals survived to scheduled necropsy, exhibited no adverse clinical observations due to treatment, and gained weight at the same rate throughout the study. Histopathological evaluation of Group 1 lung samples was consistent with unabated tumor growth. Group 2 exhibited regression in 10% of animals (n = 2/20). IH NanoPac-treated groups exhibited significantly higher tumor regression incidence per group (n = 11-13/20; p < 0.05, χ2). IHC subset analysis revealed tumor-nodule cluster separation, irregular borders between tumor and non-neoplastic tissue, and an increased density of infiltrating CD11b+ cells in Group 2 animals (n = 2/3) and in all IH NanoPac-treated animals reviewed (n = 3/3 per group). A single animal in Group 4 and Group 6 exhibited signs of pathological complete response at necropsy with organizing stroma and immune cells replacing areas presumed to have previously contained adenocarcinoma nodules. Conclusion: Tumor regression and immune cell infiltration were observed in all treatment groups, with an increased incidence noted in animals receiving IH submicron particle paclitaxel treatment.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Paclitaxel/administration & dosage , Administration, Inhalation , Albumins/administration & dosage , Animals , Antineoplastic Agents, Phytogenic/pharmacology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Lung Neoplasms/pathology , Male , Paclitaxel/pharmacology , Rats , Rats, NudeABSTRACT
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. Animals were followed for tumor growth and clinical signs. At necropsy, 786-O and UM-UC-3 tumor-site tissues were evaluated by H&E and IHC and analyzed by LC-MS/MS for docetaxel concentration. Two and 3 cycles of IT-NanoDoce® significantly reduced UM-UC-3 tumor volume (p < 0.01) and eliminated most UM-UC-3 and 786-O tumors. In both models, NanoDoce® treatment was associated with (peri)tumor-infiltrating immune cells. Lymphoid structures were observed in IT-NanoDoce®-treated UM-UC-3 animals adjacent to tumor sites. IT-vehicle and IV-docetaxel exhibited limited immune-cell infiltration. In both studies, high levels of docetaxel were detected in NanoDoce®-treated animals up to 50 days post-treatment. In the PC-3 study, IT-NanoDoce® and IV-docetaxel resulted in similar tumor reduction. NanoDoce® significantly reduced tumor volume compared to IT-vehicle in all xenografts (p < 0.0001). We hypothesize that local, persistent, therapeutic levels of docetaxel from IT-NanoDoce® reduces tumor burden while increasing immune-cell infiltration. IT NanoDoce® treatment of prostate, renal and bladder cancer may result in enhanced tumoricidal effects.
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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 2.9 mg/kg (IVnP), inhaled NanoPac low dose (IHNP-LD) at 0.38 mg/kg, or inhaled NanoPac high dose (IHNP-HD) at 1.18 mg/kg. Plasma and lung tissue paclitaxel concentrations were determined using ultraperformance liquid chromatography tandem mass spectrometry from animals sacrificed at 10 time points ranging up to 2 weeks after administration. Peak concentration (Cmax), apparent residence half-life (T1/2), exposure (AUC(last)), and dose-normalized exposure (AUCD(last)) were determined. Pulmonary histopathology was performed on rats sacrificed at the 336-hour time point. RESULTS: Paclitaxel was detectable and quantifiable in the rat lung for both inhaled NanoPac arms sampled at the final necropsy, 336 hours postadministration. Substantial paclitaxel deposition and retention resulted in an order of magnitude increase in dose-normalized pulmonary exposure over IVnP. Inhaled NanoPac arms had an order of magnitude lower plasma Cmax than IVnP, but followed a similar plasma T1/2 clearance (quantifiable only to 72 hours postadministration). Pulmonary histopathology found all treated animals indistinguishable from treatment-naive rats. CONCLUSION: In the rodent model, inhaled NanoPac demonstrated substantial deposition and retention of paclitaxel in sampled lung tissue. Further research to determine NanoPac's toxicity profile and potential efficacy as lung cancer therapy is underway.
Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Lung/metabolism , Paclitaxel/administration & dosage , Administration, Inhalation , Albumins/administration & dosage , Albumins/pharmacokinetics , Animals , Antineoplastic Agents, Phytogenic/pharmacokinetics , Area Under Curve , Dose-Response Relationship, Drug , Half-Life , Male , Paclitaxel/pharmacokinetics , Rats , Rats, Sprague-Dawley , Time Factors , Tissue DistributionABSTRACT
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 × 4.0 cm area on the lateral surface of a guinea pig using lead shielding. Guinea pigs were exposed to a single fraction of X-ray irradiation ranging from 25-79 Gy via an XRAD320ix Biological Irradiator with the collimator removed. Gross skin changes were measured using clinical assessments defined by the Kumar scale. Skin contracture was assessed, as well as histological evaluations. RESULTS: Loss of dermal integrity was shown after a single dose of soft X-ray radiation at or above 32 Gy with the central 2.0 × 2.0 cm of the exposed site being the most affected. Hallmarks of the skin injury included moist desquamation, ulceration and wound contracture, as well as alterations in epithelium, dermis, muscle and adipose. Changes in the skin were time- and radiation dose-dependent. Full-thickness injury occurred without animal mortality or gross changes in the underlying organs. CONCLUSIONS: The guinea pig is an appropriate small animal model for the short-term screening of countermeasures for cutaneous radiation injury (CRI).
Subject(s)
Disease Models, Animal , Radiodermatitis/etiology , Radiodermatitis/pathology , Skin/pathology , Skin/radiation effects , X-Rays/adverse effects , Animals , Dose-Response Relationship, Radiation , Guinea Pigs , Radiation Dosage , Radiodermatitis/physiopathology , Skin/physiopathologyABSTRACT
PURPOSE: We evaluated the effect of the renin angiotensin system (RAS) peptide NorLeu3-Angiotensin (1-7) (NLE) formulated in a viscoelastic gel (USB004) on the healing of full-thickness corneal injuries. METHODS: Dutch pigmented rabbits received conjunctival administration of 0.3% USB004, 0.03% USB004, or vehicle-control to healthy and full-thickness injured eyes administered once daily for 28 consecutive days. Safety was evaluated using IOP measurement, slit-lamp examination, and confocal microscopy. Evaluations for both efficacy studies included an oblique light examination, modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, confocal microscopy imaging, and histologic analysis. RESULTS: Application of 0.3% USB004, 0.03% USB004, and vehicle-control was safe in healthy and incised eyes. Further, application of 0.3% and 0.03% USB004 following full-thickness corneal incision resulted in a 2-fold acceleration of resolution of edema and inflammation, reduction in duration of wound leakage on a modified Seidel test (Seidel test with gentle ocular pressure) as well as during elevated IOP test, and healing with near normal architecture without evidence of fibrosis and angiogenesis when compared to vehicle-control animals. CONCLUSIONS: Topical ocular application of 0.3% and 0.03% USB004 promotes full-thickness cornea wound healing without the evidence of fibrosis and angiogenesis. Further studies are warranted to determine the cornea-specific mechanism of action(s) that promotes regeneration leading to clear corneal healing.
Subject(s)
Angiotensin II/therapeutic use , Corneal Injuries/drug therapy , Peptide Fragments/therapeutic use , Wound Healing/drug effects , Administration, Ophthalmic , Animals , Cicatrix/prevention & control , Cornea/ultrastructure , Intraocular Pressure/drug effects , Microscopy, Confocal , Microscopy, Electron, Scanning , Rabbits , Slit LampABSTRACT
Significance: 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. Recent Advances: 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. A novel topical agent that accelerates healing and increases the proportion of fully healed DFUs, DSC127 [aclerastide; active ingredient, NorLeu3-angiotensin (1-7) (NorLeu3-A(1-7))], is recruiting patients in Phase III clinical trials (NCT01830348 and NCT01849965). NorLeu3-A(1-7) is an analog of the naturally occurring peptide, angiotensin 1-7. The mechanisms of action include induction of progenitor proliferation, accelerated vascularization, collagen deposition, and re-epithelialization. Critical Issues: Current modalities for the treatment of DFUs include strict offloading, bandaging, debridement and, on a limited basis, application of Regranex. Novel potent therapies are needed to combat this significant burden to the diabetic patient and the healthcare system. Future Direction: Preclinical and clinical research shows that DSC127 is highly effective in the closure of diabetic wounds and is superior to Regranex in animal studies. Clinical development of DSC127 as a topical agent for the healing of DFU is underway. Further investigation into the mechanisms by which this product accelerates healing is warranted.
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PURPOSE: This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. METHODS: Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). RESULTS: Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. CONCLUSIONS: Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.
Subject(s)
Nanoparticles/administration & dosage , Nanoparticles/adverse effects , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Peritoneal Neoplasms/drug therapy , Adult , Aged , Dose-Response Relationship, Drug , Female , Humans , Infusions, Parenteral , Male , Middle Aged , Nanoparticles/metabolism , Paclitaxel/pharmacokinetics , Peritoneal Neoplasms/metabolismABSTRACT
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. TUNEL staining revealed that the CRBI 6 Gy group had a delayed and increased apoptotic response. This correlated with decreased recovery of live cells as compared to the other injuries. Similar response was observed when cleaved-caspase-3 immunohistochemical staining was compared between CRBI 6 Gy and thermal injury. TNFR1, caspase 8, Bax and IL-6 mRNA expression revealed that the higher CRBI group had delayed increase in mRNA expression as compared to thermal injury alone. RIPK1 mRNA expression and necrotic cell counts were delayed in the CRBI 6 Gy group to day 5. TNF-α and NFκB expression peaked in the CRBI 6 Gy group at day 1 and was much higher than the other injuries. Also, inflammatory cell counts in the CRBI 6 Gy group were lower at early time points as compared to thermal injury by itself. These data suggest that CRBI delays and exacerbates apoptosis and inflammation in skin as well as increases necrosis thus resulting in delayed wound healing.
Subject(s)
Apoptosis/radiation effects , Burns/pathology , Radiation Injuries, Experimental/pathology , Radiation Injuries/metabolism , Skin/radiation effects , Animals , Biomarkers/metabolism , Burns/metabolism , Inflammation/metabolism , Male , Mice, Inbred C57BL , Necrosis/metabolism , Radiation Injuries, Experimental/metabolism , Skin/metabolism , TranscriptomeABSTRACT
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. METHODS: A total of 68 subjects with herniated lumbar disk were enrolled and randomized into treatment (surgery plus gel) or surgery-only control groups. A prospective statistical analysis assessed the effect of gel in the severe back pain subgroup (prespecified as greater than or equal to median baseline back pain of the population studied). All subjects except 2 controls lost to follow-up completed the study. Preoperative and postoperative visual analogue scale leg pain scores were analyzed and compared between groups at 60 days after surgery. RESULTS: There were no serious adverse events or neurological safety concerns reported in any patients. Gel-treated patients had statistically significantly lower visual analogue scale leg pain scores at study end compared with controls (P=0.0240), representing a 21% additional reduction in leg pain compared with surgery alone in the severe baseline back pain subgroup (P=0.0240). The proportion of subgroup patients experiencing zero leg pain at study end was significantly higher in the gel treatment group (60%) than in the control group (23%) (P=0.0411). CONCLUSIONS: The data from this study confirm and extend results of 2 previous studies in Italy and the United States that reported statistically significantly greater reductions in leg pain in gel-treated patients with severe preoperative low back pain compared with patients who only underwent decompression surgery.