Amifostine (Ethyol, WR-2721) is a cytoprotective drug approved by the US Food & Drug Administration for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The primary objective of this project was to develop orally active amifostine nanoparticles using spray drying technique. Two different nanoparticle formulations (Amifostine-PLGA (0.4:1.0 and 1.0:1.0)) were prepared using a Buchi B191 Mini Spray Dryer. A water-in-oil emulsion of amifostine and PLGA (RG 502) was spray dried using an airflow of 600 L h(-1) and input temperature of 55 degrees C. A tissue distribution study in mice was conducted following oral administration of the formulation containing drug-polymer (0.4:1.0). The efficiency of encapsulation was 90% and 100%, respectively, for the two formulations while the median particle sizes were 257 and 240 nm, with 90% confidence between 182 and 417 nm. Since amifostine is metabolized to its active form, WR-1065, by intracellular alkaline phosphatase, the tissue levels of WR-1065 were measured, instead of WR-2721. WR-1065 was detected in significant amounts in all tissues, including bone marrow, jejunum and the kidneys, and there was some degree of selectivity in its distribution in various tissues. This work demonstrates the feasibility of developing an orally effective formulation of amifostine that can be used clinically.
"A sizable effort has been made by various researchers/research groups to make amifostine more ‘user-friendly’, largely by attempting to reduce drug toxicity while preserving the drug’s overall radioprotective attributes. These efforts include attempts to (a) chemically reengineer amifostine into a new, better tolerated analog (Davidson et al. 1980, Brown et al. 1988); (b) improve methods and vehicles of drug delivery (Fatome et al. 1987, Srinivasan et al. 2002, Pamujula et al. 2004); (c) foster radioprotective synergy by supplementing lower doses amifostine with less toxic (but generally less protective) protectants (e.g., alpha-tocopherol) (Srinivasan et al. 1992); (d) control amifostine toxicity by direct pharmacologic means (i.e., use of antiemetics) (Seed et al. unpublished observations); and (e) use very low, presumably non-toxic doses of amifostine solely for the purpose of protecting against radiation-induced mutatagenesis and/or carcinogenesis, while foregoing the drug’s cytoprotective attributes that requires much higher, more toxic doses to be delivered (Grdina et al. 2002). "
[Show abstract][Hide abstract] ABSTRACT: Purpose
Amifostine is a highly efficacious cytoprotectant when administered in vivo at high doses. However, at elevated doses, drug toxicity manifests for general, non-clinical radioprotective purposes. Various strategies have been developed to avoid toxic side-effects: The simplest is reducing the dose. In terms of protecting hematopoietic tissues, where does this effective, non-toxic minimum dose lie?
Material and methods
C3H/HEN mice were administered varying doses of amifostine (25–100 mg/kg) 30 min prior to cobalt-60 irradiation and euthanized between 4–14 days for blood and bone marrow collection and analyses.
Under steady-state, amifostine had little effect on bipotential and multi-potential marrow progenitors but marginally suppressed a more primitive, lineage negative progenitor subpopulation. In irradiated animals, prophylactic drug doses greater than 50 mg/kg resulted in significant regeneration of bipotential progenitors, moderate regeneration of multipotential progenitors, but no significant and consistent regeneration of more primitive progenitors. The low amifostine dose (25 mg/kg) failed to elicit consistent and positive, radioprotective actions on any of the progenitor subtypes.
Radioprotective doses for amifostine appear to lie between 25 and 50 mg/kg. Mature, lineage-restricted progenitors appear to be more responsive to the protective effects of low doses of amifostine than the more primitive, multipotential progenitors.
International Journal of Radiation Biology 03/2014; 90(7). DOI:10.3109/09553002.2014.899450 · 1.69 Impact Factor
"To harness the convenience of the oral delivery of amifostine while retaining drug efficacy, Pamujula et al (2004) developed an orally active biodegradable sustained-release formulation of amifostine using poly (lactide-co-glycolide) (PLGA) as carrier particles using a spray drying technique. A murine model was utilized to demonstrate that the amifostine nanoparticles given orally delivered the drug in significant concentrations to a variety of tissues, including key target tissues, with some degree of selectivity. "
[Show abstract][Hide abstract] ABSTRACT: Amifostine (ethiofos, WR-2721) is an organic thiophosphate prodrug that serves as an antineoplastic adjunct and cytoprotective agent useful in cancer chemotherapy and radiotherapy. The selective protection of certain tissues of the body is believed to be due to higher alkaline phosphatase activity, higher pH and vascular permeation of normal tissues. Amifostine is conventionally administered intravenously before chemotherapy or radiotherapy. It is approved by the Food and Drug Administration (FDA) to reduce cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer. It was originally indicated to reduce the cumulative renal toxicity from cisplatin in non-small cell lung cancer although this indication was withdrawn in 2005. Amifostine is also FDA approved for patients with head and neck cancer to reduce the incidence of moderate to severe xerostomia in patients who are undergoing postoperative radiation treatment where the radiation port includes a substantial portion of the parotid glands. The potential of amifostine as a cytoprotective agent is unlikely to be fully realized if the method of administration is restricted to intravenous administration. Attempts have been made to develop non-invasive methods of delivery such as transdermal patches, pulmonary inhalers, and oral sustained-release microspheres. It is the goal of this article to explore non-intravenous routes of administration associated with better efficacy of the drug. This review will primarily focus on the variety of more recently studied (2002 and later) alternative modes for amifostine administration, including subcutaneous, intrarectal and oral routes.
Journal of Pharmacy and Pharmacology 08/2008; 60(7):809-15. DOI:10.1211/jpp.60.7.0001 · 2.26 Impact Factor
"Spray-dried poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles have been investigated for oral delivery of amifostine (Pamujula et al., 2004), an organic thiophosphate prodrug that is metabolized by tissue alkaline phosphatase into active thiol metabolite. When administered orally to mice, the amifostineencapsulated PLGA nanoparticles promoted absorption and the drug was present in blood and other highly-perfused tissues within 30 min of administration. "
[Show abstract][Hide abstract] ABSTRACT: Cancer is the second leading cause of morbidity and mortality in the United States, with occurrences portraying an upward
trend for the future. In 2007, approximately 10 million cases of cancer will occur globally, with a total of around 1.5 million
new cancer cases and over 560,000 deaths expected in the United States (U.S. National Institute of Health, 2006). Strikingly,
remarkable advances in diagnosis and therapy of cancer have been made over the past few decades resulting from significant
advances in fundamental cancer biology. What lacks in this case is clinical translation of these advances into effective therapies.
A major hurdle in cancer diagnosis and therapy is the targeted and efficacious delivery of agents to the tumor site, while
avoiding adverse damage resulting from systemic administration. While systemic drug delivery already hinges largely on physicochemical
properties of the drug, such as size, diffusivity, and plasma protein binding affinity, tumors possess a dense, heterogeneous
vasculature and an outward net convective flow that act as hurdles to efficient drug deposition at the target site (Jang et
al., 2003). Nanocarriermediated delivery has emerged as a successful strategy to enhance delivery of therapeutics and imaging
agents to tumors, thereby increasing the potential for diagnosis at an earlier stage or for therapeutic success (or both).
Based on the initial observation by Maeda and Matsumura that tumors possess a fenestrated vasculature, with pores on average
ranging between 200 and 800 nm, and a lack of lymphatic drainage, together termed the enhanced permeability and retention
(EPR) effect, it was found that colloidal carriers in the nanometer size range could target tumors passively, by specific
extravasation through these fenestrations, and are retained at the site for prolonged time because of lack of lymphatic drainage
(Matsumura and Meada, 1986). This physiological advantage has been used successfully to enhance delivery of diagnostic and
therapeutic agents, leading to the U.S. Food and Drug Administration (FDA) approval of nanoparticle formulations such as Feridex®
for diagnostic applications and Doxil® and Abraxane® for cancer therapy (U.S. Food and Drug Administration, 2006).
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