Challenges in oral docetaxel delivery, and how nanotechnology may be the answer

Experts recently reviewed challenges and advances in the oral delivery of hydrophobic anticancer drugs, particularly docetaxel, and discussed how a nanotechnology-based drug-delivery system could overcome the major barriers that these agents encounter. The findings were published in the International Journal of Nanomedicine.

“Recent advances in pharmaceutical research have focused on designing new and efficient drug-delivery systems for site-specific targeting, thus leading to improved bioavailability and pharmacokinetics,” wrote the authors, led by Muhammad Farhan Sohail, PhD, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Lahore Campus, Lahore, Pakistan.

Oral chemotherapy benefits

Overall, 65% of cancer deaths occur in developing countries, where people are exposed to increased population growth, carcinogens, and poor hygiene. Current cancer treatment often involves a regimen of chemotherapy, radiotherapy, and surgery to completely clear tumor cells. Most anticancer drugs are administered intravenously, which is expensive and labor intensive.

Oral drug delivery is a more convenient method of treatment administration, but it is limited by first-pass metabolism, poor solubility, efflux transport, low intrinsic permeability of drug limits, bioavailability of drugs, and more. Nevertheless, according to the authors, “The oral delivery of chemotherapeutic drugs is highly desirable in terms of its convenience in synthesis and administration, ease of design, vast variety of formulations and, most importantly, better patient compliance in terms of chronic ailments.”

Oral delivery of docetaxel

Docetaxel, a hydrophobic chemotherapy drug, inhibits cell replication by interfering with microtubule networks. It is more effective than paclitaxel, and displays antitumor activity against an array of cancer types.

Rate-limiting factors governing the bioavailability of docetaxel include breakdown in acidic gastric fluid and permeation across the enterocytes.

Commercially available, intravenous docetaxel combined with polysorbate 80 (Tween^® 80), a nonionic surfactant that improves aqueous solubility, is an FDA-approved formulation. However, polysorbate 80 poses health risks, including hypersensitivity reactions and adverse cardiovascular effects.

Tween 80 interferes with the pharmacokinetic properties of docetaxel, thus increasing the concentration of unbound docetaxel in the plasma. Also, high plasma levels of Tween 80 can reduce the plasma clearance of docetaxel, leading to severe hematologic toxicity caused by the unbound drug.

These issues support strong demand for the development of docetaxel formulations without polysorbate 80, according to the authors.

Improving oral delivery of docetaxel

“Developing Tween 80-free formulations with improved pharmacokinetics, pharmacodynamics, and better tumor targeting has led to several new possibilities,” wrote the reviewers.

For example, docetaxel could be co-administered with other drugs that boost oral bioavailability, such as cyclosporine A. In animal models, co-administration with cyclosporine A boosted plasma concentration of docetaxel by 14% to 17%, and it caused a 17-fold reduction in plasma clearance.   

Researchers have also assessed how docetaxel and other chemotherapeutic agents could be administered by nanotechnology-delivery systems, such as liposomes, prodrugs, core-shell polymeric nanoparticles (NPs), metallic NPs, and solid lipid NPs. Various materials can be used to time the delivery of docetaxel, including polymers, lipids, inorganic materials, metals, and proteins or the hybrids.

The authors proposed five advantages to drug delivery using nanotechnology:

• Improved bioavailability by surmounting solubility or permeability barriers
• Protection of the drug from unfavorable environments (eg, enzymatic degradation)
• Improved tumor targeting
• Site-specific release
• Co-delivery of drugs and diagnostic agents

Specifically, the reviewers posited that nanotechnology-based drug-delivery systems could boost the pharmacokinetics and pharmacodynamics of docetaxel by enhancing dissolution, increasing mucosal permeation, and blocking P-gp efflux pump or pre-systemic metabolism.

“The results achieved so far using different nano-based delivery systems seem to be very encouraging and promising to increase the oral bioavailability of [docetaxel], along with increasing its pharmacokinetics and improving its toxicity properties manifold,” the researchers concluded. “Furthermore, sincere efforts are being made in understanding the cellular interactions of various formulations and the mechanisms of their efficacy and safety profile.”