Elsevier

Journal of Controlled Release

Volume 200, 28 February 2015, Pages 138-157
Journal of Controlled Release

Review
Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications

https://doi.org/10.1016/j.jconrel.2014.12.030Get rights and content

Abstract

Cancer is a leading cause of death worldwide. Currently available therapies are inadequate and spur demand for improved technologies. Rapid growth in nanotechnology towards the development of nanomedicine products holds great promise to improve therapeutic strategies against cancer. Nanomedicine products represent an opportunity to achieve sophisticated targeting strategies and multi-functionality. They can improve the pharmacokinetic and pharmacodynamic profiles of conventional therapeutics and may thus optimize the efficacy of existing anti-cancer compounds. In this review, we discuss state-of-the-art nanoparticles and targeted systems that have been investigated in clinical studies. We emphasize the challenges faced in using nanomedicine products and translating them from a preclinical level to the clinical setting. Additionally, we cover aspects of nanocarrier engineering that may open up new opportunities for nanomedicine products in the clinic.

Introduction

For more than two decades, advances in understanding cancer biology have only slowly been translated into significant improvements in cancer care. The World Health Organization (WHO) attributed 8.2 million deaths to cancer in 2012, which constituted 13% of all deaths. Within the next two decades, new global cancer incidences are expected to increase from 14 million in 2012 to as many as 22 million. One of the main reasons is the lack of selective delivery of anti-cancer compounds to neoplastic tissue. High systemic exposure to anti-neoplastic agents frequently results in dose-limiting toxicity. Therefore, targeted delivery is of utmost importance in order to overcome current limitations in cancer therapy. Recent developments in nanotechnology are expected to improve drug delivery, thereby increasing efficacy while decreasing the side effects of anti-cancer drugs.

Nanocarriers2 have unique properties such as nanoscale size, high surface-to-volume ratio, and favorable physico-chemical characteristics. They have the potential to modulate both the pharmacokinetic and pharmacodynamic profiles of drugs, thereby enhancing their therapeutic index. Loading of drugs into nanocarriers can increase in vivo stability, extend a compound's blood circulation time, and allow for controlled drug release. Thus, nanomedicine compounds can alter the biodistribution of drugs by allowing them to accumulate preferably at the tumor site. This phenomenon is known as enhanced permeability and retention effect (EPR) (Section 2.2.1).

A wide range of nanomaterials based on organic, inorganic, lipid, protein, or glycan compounds as well as on synthetic polymers have been employed for the development of new cancer therapeutics (Fig. 3). According to the registry maintained by clinicaltrials.gov, a total of 1575 nanomedicine formulations (search terms ‘liposome’/‘nanoparticle’/‘micelle’) had been registered for clinical trials by December 2014. As many as 1381 of these are in the field of cancer therapy [1] (Fig. 1B). However, most clinical trials focus on marketed products, such as liposomal doxorubicin or albumin-bound paclitaxel. Either new indications or therapies in combination with other anti-cancer agents are investigated. Our search of the key word ‘cancer nanoparticles’ in Web of Science® yielded 57,944 publications available in December 2014 (Fig. 1A). This illustrates the huge gap between technical and clinical development. There are concerns that a delay in clinical development of new nanomedicine drugs may be detrimental to cancer patients. With this in mind, we discuss in this review the recent developments of nanomedicine therapeutics in early and late clinical trials. We cover opportunities to develop next-generation clinical nanomedicine therapeutics with advanced functionalities. In addition, we address challenges encountered during drug development and regulatory approval.

Section snippets

Rationale for the development of nanomedicine products for cancer therapy

There are convincing arguments in favor of developing nano-sized therapeutics [2].

First, nanoparticles may help to overcome problems of solubility and chemical stability of anti-cancer drugs. Poor water solubility limits the bioavailability of a compound and may hamper the development of anti-cancer agents identified during early drug screens [3]. Uptake and delivery of poorly soluble drugs may be increased by enveloping the compound in a hydrophilic nanocarrier. At the same time, this may

Nanomedicine in clinical cancer care

Various types of nanomedicine compounds have been used in clinical cancer care, including viral vectors, drug conjugates, lipid-based nanocarriers, polymer-based nanocarriers, and inorganic nanoparticles (Fig. 3) [2]. The different nanomedicine products are discussed below, with special emphasis placed on clinical trials. Most nanomedicine therapeutics are investigated in phase 1 trials in patients with solid tumors. Specific cancer indications are explored in advanced (phases 2 and 3) clinical

Challenges and current limitations

Nanomedicine is as one of the most promising and advanced approaches in the development of frontier cancer treatment. Thousands of publications suggest that nanomedicine therapeutics are effective in cancer treatment, both in vitro and in vivo (Fig. 1A). However, only very few nanocarrier-based cancer therapeutics have successfully entered clinical trials (Fig. 1B). Thus, it is important to address the challenges in developing optimized nanomedicine products for clinical use [139].

Conclusions

Nanomedicine represents one of the fastest growing research areas and is regarded as one of the most promising tools for frontier cancer treatment. Several nanomedicine platforms have been developed and many are used in clinical cancer care. The most important advantages and disadvantages of the different strategies are summarized in Table 7. This table provides an expert opinion on clinical opportunities and summarizes preferred applications for the discussed technologies. Several phase 3

Acknowledgment

The authors thank Dr. Silvia Rogers for editorial assistance and Andrea Fehrenbach for graphic support. Financial support was provided by the Swiss Centre of Applied Human Toxicology (SCAHT).

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    Both authors contributed equally to this work.

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