Intraprostatic Chemotherapy: Distribution and Transport Mechanisms

Abstract

Purpose:The present study evaluated the tissue distribution and targeting advantage of intraprostatic chemotherapy. Experimental Design: We studied the delivery and spatial distribution of a fluorescent drug, doxorubicin, in the prostate of beagle dogs, after intraprostatic or i.v. administration. Drug concentrations were measured using high-performance liquid chromatography and confocal fluorescence microscopy. Results: I.v. and intraprostatic injections yielded qualitatively and quantitatively different doxorubicin distribution in the prostate. A relatively homogeneous distribution was found after i.v. administration, whereas intraprostatic injection yielded a highly heterogeneous distribution with >10-fold higher concentrations localized in a cone-shaped glandular lobule bound by fibromuscular stroma, compared with other parts of the prostate. Compared with i.v. injection, intraprostatic injection yielded, on average, f100-fold higher tissue-to-plasma concentration ratio, ranging from 963-fold near the injection site to 19-fold in the contralateral half of the prostate. The drug distribution within the prostate further suggests an important role for acinar flow in intraprostatic drug transport. Conclusions: Intraprostatic administration represents a viable option to deliver high drug concentrations within the prostate. The results further suggest the fibromuscular stroma separating the prostatic lobules as a major barrier to drug transport and convective flow as an important drug transport mechanism in the prostate.

Biodegradable intraprostatic doxorubicin implants

“…Acinar fl uid formed in the lobule is emptied into the urethra through connecting ducts, creating a convective fl ow that can facilitate drug transport. This convection-facilitated transport is supported by our previous fi nding that prostate tissue penetration for the intraprostatic injection is >1 cm, 21 more than 3 times greater than the typical penetration distance mediated by diffusion alone, <0.3 cm. 22 The lack of an important physiological function of the prostate ' s glandular tissue in men who are at the older age associated with a higher incidence of prostate cancer suggests that eliminating the normal, noncancerous prostate cells is not likely to result in unacceptable toxicity; this is supported by the generally accepted radical prostatectomy approach, where the tumor and normal tissues are simultaneously removed.…”

“…The restricted, intralobular distribution is consistent with our previous observation with an intraprostatic doxorubicin infusion into a dog prostate. 21 The drug release and distribution was rapid, resulting in evenly distributed drug concentrations within the lobule after 24 hours. This may be due to the convective fl ow created by the acinar fl uid fl ow (see Introduction).…”

“…In addition, the glandular prostate is composed of a relatively small number of the anatomical structures called lobules, ~15 in the dog and 20 to 70 in humans. 21 These cone-shaped structures are widest at the prostatic capsule and narrow as they approach the E242 urethra. Acinar fl uid formed in the lobule is emptied into the urethra through connecting ducts, creating a convective fl ow that can facilitate drug transport.…”

The Roles of Tight Junctions and Claudin-1 in the Microbubble-Mediated Ultrasound-Induced Enhancement of Drug Concentrations in Rat Prostate

“…Although this structure may be the major factor leading to the failure of treatment of CP, the main components are unclear (Shang et al 2014a, b). The drugs from the blood to the prostate cavity mainly passes through capillary endothelial cells, fibrous tissue, basement membrane, and glandular epithelium cells (Wientjes et al 2005); hence, one or more of these components are the main structure of regulating the permeability of the prostate. Regardless of the components of this barrier structure, the main structures which regulate the tissue permeability include the transcellular and paracellular pathways.…”

Intraprostatic ethanol diffusion: comparison of two injection methods using ex vivo human prostates

“…2 In addition, intraprostatic drug delivery has been evaluated as a potential treatment option for localized prostate cancer and chronic pelvic pain syndrome in men. 3,4 To date, clinical trials investigating injectable agents include ethanol, botulinum toxin, as well as apoptosis and proteolysis-inducing agents. 5 Intraprostatic injection of anhydrous ethanol (AE) has shown promise in the treatment of BPH; however, clinical trials documented variable outcomes.…”