In vivo controlled release of fenretinide from long-acting release depots for chemoprevention of oral squamous cell carcinoma recurrence

Abstract

Local, long-acting release fenretinide (4HPR) millicylindrical implants were prepared and evaluated for their release kinetics in vivo and their ability to suppress oral cancer tumor explant growth. Poly(lactic-co-glycolic acid)(PLGA) implants were prepared as a function of drug loading and the presence of various excipients (pore-formers, solubilizers, crystallization inhibitors) to enhance release of the insoluble 4HPR. Release kinetics and bioerosion of PLGA were monitored both in vitro in a PBS/Tween 80 buffer and in vivo by recovery of the drug remaining at the injection site. 4HPR was released from PLGA implants much slower in vivo than in the drug solubilizing media in vitro, with a 3-week lag phase and continuous release of >2 months, but showed some release enhancement by addition of solubilizers. Water-soluble PVA/sucrose implants for release of 4HPR served to determine if drug dissolution provided suitable controlled release without the PLGA, and this formulation showed continuous drug release over 6 weeks in vivo. Placement of PLGA-4HPR implants adjacent to oral cancer tumor murine xenografts showed inhibition of tumor growth relative to sham implants, indicating the potential for the local 4HPR delivery approach to be useful for oral cancer chemoprevention.

Design, Synthesis, Radiosynthesis and Biological Evaluation of Fenretinide Analogues as Anticancer and Metabolic Syndrome‐Preventive Agents

“…Taken together, our preliminary results suggest that 2b and 3b might represent promising anti-cancer agents to be tested in vivo. 43 see Supporting Information for more details) without dramatically affecting the in vitro behaviour, as confirmed by our preliminary in vitro results. Importantly, the low bioavailability of 4-HPR is mostly related to the hydrophobic nature of the molecule.…”

Leukoplakia and Immunology: New Chemoprevention Landscapes?

“…Two treatment options can be considered to reduce the systemic toxicity and improve the local amount of drug or target drug. As suggested by Nieto et al, a first option is to use alternative methods to deliver chemopreventive drugs to the oral mucosa [116,117]. The second option is the combined use of an agent endowed with complementary antitumor activities.…”

Microemulsion for Prolonged Release of Fenretinide in the Mammary Tissue and Prevention of Breast Cancer Development

“…Second, previous studies demonstrated that topical drug administration to the breast skin (thus, in close proximity to the mammary tissue) resulted in similar breast distribution compared to oral administration but lower plasma levels . Finally, subcutaneous administration of fenretinide-loaded PLGA implants placed alongside of oral squamous cell carcinoma tumors inhibited tumor xenographs with local controlled release, supporting the applicability of local fenretinide administration for chemoprevention …”

“…Since lipophilicity has been described as one of the main correlates of in vivo volume of distribution ( V d ), with V d increasing with lipophilicity, it is reasonable to expect that fenretinide might remain locally retained for longer periods of time compared to Alexa Fluor. Additionally, with the possibility of fenretinide slower dissolution in fluids in vivo , its tissue binding and accumulation in the breast and subcutaneous tissues support its longer retention. ,,, …”

“…For example, monoacylglycerol-based liquid crystals are susceptible to lipolysis by a variety of enzymes, which attack the ester bond present on the lipid chain that links the acyl chain to the glycerol backbone, increasing drug release . Considering that phospholipid-based carriers are also susceptible to enzymatic hydrolysis, it would be reasonable to suggest that in vivo drug release from this formulation might be faster than in vitro ; − however, fenretinide tissue binding and high lipophilicity (which has been suggested to delay its dissolution in vivo ) may further prolong its mammary tissue retention.…”