Biodegradable intraprostatic doxorubicin implants

Abstract

Systemic chemotherapy is not effective in the treatment of prostate-confi ned cancer. We developed biodegradable, doxorubicin-loaded cylinders for intraprostatic implantation and evaluated the feasibility of using regional intraprostatic drug therapy to treat prostate-confi ned cancer. Cylinders were prepared using poly(lactide-co-glycolide) (PLG) or PLG co polymers. The in vitro and in vivo drug release, intraprostatic pharmacokinetics, and histopathology in dogs implanted with the cylinders were studied. The doxorubicin-loaded cylinders made of PLG polymers of 7.9 to 54 kDa molecular weight (MW) had a diameter of ~800 m m, drug loading of 10% to 30% (wt/wt), and even distribution of crystalline drug throughout the matrix. Burst release varied from 3% to 73%, and 7-day cumulative release from 4% to 90%. Decreasing polymer MW and increasing drug loading were associated with higher initial burst release and overall release rates. The in vivo drug release from cylinders (33-kDa PLG, 30% drug loading) in dog prostates was rapid (~80% in 48 hours). Spatial drug distribution, visualized using confocal fl uorescence microscopy, showed high concentrations confi ned to the lobule containing the implant (referred to as the implanted lobule), with steep concentration gradients over the septa separating the lobules. Concentrations in the implanted lobule were about 8 times higher than concentrations delivered by an intravenous injection. The implants caused necrotic cell death in the implanted lobule, without damage to prostatic nerve bundles or the urethra. These results indicate the feasibility of using biodegradable PLG cylinders as intraprostatic implants to selectively deliver high drug concentrations to prostate tissue.

Polyelectrolyte micro- and nanoparticles with doxorubicin

“…The release of Dox from the particles increases with the increasing pH of their formation (this effect results from the formation of a more stable polyelectrolyte complex at lower pH) and with the increasing number of polymer layers. The physicochemical properties of the polyelectrolyte microparticles with the (Dox-DS 100 )-Chit 400 com position indicate that they can be used to deliver Dox to tumors in different locations (locally or regionally), such as bladder tumors (the walls of the bladder are covered with a layer of mucin [26,27]) or prostate tumors [28]. However, only further in vitro and in vivo studies may confirm or disprove this idea.…”

Intratumoral Delivery of β-Lapachone via Polymer Implants for Prostate Cancer Therapy

“…Besides Gliadel® wafers as we have mentioned before (35), Wientjes et. al., developed a doxorubicin-releasing poly(lactide-co-glycolide) (PLG) implant for the treatment of prostate tumors, demonstrating feasibility for in vivo use as well as low systemic concentrations of the drug after implantation into the prostate of beagle dogs (36). Recently, we reported β-lap-loaded millirods with tailorable release kinetics depending on inclusion of excipient molecules (e.g., glucose) or complexation with different cyclodextrin complexes (e.g., α-CD, β-CD, and γ-CD) (23).…”

A Totally Absorbable Multilayer PLGA Implant Device Containing Doxorubicin Inhibited Tumor Growth and Metastasis without Systemic Toxicity in Murine Breast Cancer and an Ideal Pharmacological Paradigm for Regional Chemotherapy

“…To mix doxorubicin with PLGA and place it near a tumor as cancer treatment is not a novel idea [13] [27] [28]. Our premise of layered membrane sought to overcome the technical challenge of the initial burst release of doxorubicin impregnated PLGA.…”

“…For example, Ortiz et al made a cylindrical PLGA implant of 0.8 mm diameter × 8 mm long containing doxorubicin for placement in dog prostate [13]. The production process involved extrusion and required an elevated temperature.…”