The achievement of ligand-functionalized organic/polymeric nanoparticles for treating multidrug resistant cancer

ABSTRACT

Introduction: The effectiveness of conventional cancer chemotherapy is hampered by the occurrence of multidrug resistance (MDR) in tumor cells. Although many studies have reported the development of novel MDR chemotherapeutic agents, clinical success is lacking owing to the high associated toxicity. Nanoparticle-based delivery of chemotherapeutic drugs has emerged as alternative approach to treat MDR cancers via exploitation of leaky vasculature in the tumor microenvironment. Accordingly, functionalization of nanoparticles with target specific ligands can be employed to achieve significant improvements in the treatment of MDR cancer.

Areas covered: This review focuses on the recent advances in the functionalization of nanocarriers with specific ligands, including antibodies, transferrin, folate, and peptides to overcome MDR cancer. The limitations of effective ligand-functionalized nanoparticles as well as therapeutic successes in ligand targeting are covered in the review.

Expert opinion: Targeting MDR tumors with ligand-functionalized nanoparticles is a promising approach to improve the treatment of cancer. With this approach, higher drug concentrations at targeted sites would be achieved with lower dosage frequencies and reduced side effects in comparison to existing formulations of chemotherapeutic drugs. However, potential toxicities and immunological responses to ligands should be carefully reviewed for viable options in for future MDR cancer treatment.

KEYWORDS:

• MDR
• ligand
• nanoparticle
• cancer
• overcoming drug resistance

Article highlights

• Conventional cancer treatments are hampered by the non-specific, promiscuous interactions of chemotherapeutics with both healthy and cancer cells. Most chemotherapeutics administered in solution are intolerable (severe side effects) to patients even at low concentrations and suffer from rapid systemic clearance. In addition, the penetration barrier existing in solid tumor also prevented the effective drug delivery to targeted site thus resulting low bioavailability as well as promoted MDR development in cancer cells.

• Ligand mediated nanoparticles (i.e transferrin, peptide, folate, aptamers and antibody) offers an alternative method to regulate specific targeting and intracellular trafficking of drugs inside MDR cells. Functionalization of NPs with efflux pump inhibitors has been effective to promote reversal of MDR and re-sensitizes cells to drug.

• The cell-particle interactions are the initial contact which could have profound effects on cancer treatment. Some notable ligand properties that influence cell interactions and subsequent entry into cell are ligand density, net charges, ligand hydrophobicities and shape.

• Both in vitro and in vivo results demonstrated that multifunctional nanoparticles with ligand nanoparticles enhanced MDR tumor treatment compared to non-functionalized nanoparticles and drug solutions. Side effects associated with chemotherapeutic drugs are absent when mice are administered with ligand-functionalized nanoparticles.

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Declaration of interest

WH Lee is the recipient of Cancer Institute New South Wales (CINSW) Early Career Fellowship. PM Young is the recipient of an Australian Research Council Future Fellowship (project number FT110100996). D Traini is the recipient of an Australian Research Council Future Fellowship (project number FT12010063). 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.

Additional information

Funding

This paper was not funded.