Strategies for improving the intratumoral distribution of liposomal drugs in cancer therapy

ABSTRACT

Introduction: A major limitation of current liposomal cancer therapies is the inability of liposome therapeutics to penetrate throughout the entire tumor mass. This inhomogeneous distribution of liposome therapeutics within the tumor has been linked to treatment failure and drug resistance. Both liposome particle transport properties and tumor microenvironment characteristics contribute to this challenge in cancer therapy. This limitation is relevant to both intravenously and intratumorally administered liposome therapeutics.

Areas covered: Strategies to improve the intratumoral distribution of liposome therapeutics are described. Combination therapies of intravenous liposome therapeutics with pharmacologic agents modulating abnormal tumor vasculature, interstitial fluid pressure, extracellular matrix components, and tumor associated macrophages are discussed. Combination therapies using external stimuli (hyperthermia, radiofrequency ablation, magnetic field, radiation, and ultrasound) with intravenous liposome therapeutics are discussed. Intratumoral convection-enhanced delivery (CED) of liposomal therapeutics is reviewed.

Expert opinion: Optimization of the combination therapies and drug delivery protocols are necessary. Further research should be conducted in appropriate cancer types with consideration of physiochemical features of liposomes and their timing sequence. More investigation of the role of tumor associated macrophages in intratumoral distribution is warranted. Intratumoral infusion of liposomes using CED is a promising approach to improve their distribution within the tumor mass.

KEYWORDS:

• Convection enhanced delivery
• drug delivery
• imaging
• intratumoral administration
• intratumoral distribution
• liposomes
• nanoparticles
• tumor penetration

Article highlights

• A major challenge for effective liposome cancer-therapy is the inability to deliver the therapeutics throughout the entire tumor mass.

• Strategies using tumor priming or modulation of the ECM to improve the intratumoral distribution of liposome therapeutics have potential.

• At the present time, RF ablation and HIFU appear to be the best external stimuli to combine with liposome therapies for effective tumor coverage.

• Improved tumor coverage may be possible using tumor-associated macrophages and tumor-penetrating peptides to assist in the transport of liposome therapeutics within the tumor.

• Liposomes have improved intratumoral distribution and retention as compared to small molecules administered by CED.

• CED is a promising strategy to improve the intratumoral distribution of liposome therapeutics especially for brain cancer therapy.

This box summarizes key points contained in the article.

Acknowledgements

The authors would like to thank Jonathan Sumner for preparing the figures.

Declaration of interest

This work was supported by the National Institutes of Health [5P30 CA054174-16 and R01 CA131039]. B Goins, W Phillips and A Bao are co-founders and shareholders in NanoTX Therapeutics which is developing the rhenium-186 liposomes discussed in this article. The authors have no other 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 apart from those disclosed.