Advances in oral delivery of anti-cancer prodrugs

ABSTRACT

Introduction: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route.

Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed.

Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.

KEYWORDS:

• Oral delivery
• anticancer prodrugs
• polymer prodrugs
• lipid prodrugs
• peptide prodrugs
• nanocarriers

Article highlights

• Oral delivery of most of the anticancer drugs is limited by their poor aqueous solubility and poor gastrointestinal permeability that is due to extensive efflux by the P-glycoproteins (P-gp) in the small intestine.

• Modification of anticancer drugs into their prodrugs represents as one of the key approach to overcome the pharmaceutical, pharmacokinetics and pharmacodynamics challenges, which are responsible for poor deliverability of anticancer drugs via oral route.

• The prodrug concept was introduced by Albert and Harper in 1960, where they defined it as a pharmacologically inert derivative that can produce active drug molecule in vivo, enzymatically or non-enzymatically, to produce a desired therapeutic effect.

• Different categories of anticancer drugs such as platinum compounds, camptothecin analogue, gemcitabine, 5-flurouracil, paclitaxel, were developed as prodrug compounds.

• Polymer-, lipid- and amino acid conjugated anticancer drugs represent a novel classes of prodrugs, which improve their oral absorption by P-glycoprotein modulation, alteration in gastrointestinal membrane permeability and transporters mediated absorption.

• Encapsulation of anticancer prodrugs in different nanocarrier based drug delivery systems such as polymeric nanoparticles, lipid nanocapsules, polymeric micelles and self-emulsifying drug delivery system further improve their chemical stability in gastrointestinal tract vis-à-vis enable efficient absorption via carrier mediated absorption pathways.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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