Elsevier

Advanced Drug Delivery Reviews

Volume 91, 30 August 2015, Pages 7-22
Advanced Drug Delivery Reviews

The challenges facing block copolymer micelles for cancer therapy: In vivo barriers and clinical translation

https://doi.org/10.1016/j.addr.2014.10.001Get rights and content

Abstract

The application of block copolymer micelles (BCMs) in oncology has benefitted from advances in polymer chemistry, drug formulation and delivery as well as in vitro and in vivo biological models. While great strides have been made in each of these individual areas, there remains some disappointment overall, citing, in particular, the absence of more BCM formulations in clinical evaluation and practice. In this review, we aim to provide an overview of the challenges presented by in vivo systems to the effective design and development of BCMs. In particular, the barriers posed by systemic administration and tumor properties are examined. The impact of critical features, such as the size, stability and functionalization of BCMs is discussed, while key pre-clinical endpoints and models are critiqued. Given clinical considerations, we present this work as a means to stimulate a renewed focus on the unique chemical versatility bestowed by BCMs and a measured grasp of representative in vitro and in vivo models.

Introduction

The medical application of micelle-based nanotechnology dates back to the pioneering work of Speiser at the ETH in Zurich with the development of drug delivery systems for controlled release. In 1976, he explored the use of solidified micelles, termed ‘nanoparts’, and put forth that “the partition of drugs in such nanoparts seemed to be promising as a new parenteral drug delivery system for long-term therapy” [1], [2]. The principles of this seminal publication indeed led to the first drug delivery application of block copolymer micelles (BCMs) by Ringsdorf [3]. Decades later, impactful contributions by Kataoka, Kabanov and others have resulted in BCM formulations that have now reached late-stage clinical development [4], [5], [6].

BCMs are nano-sized aggregates of amphiphilic copolymers with a size range of about 10 to 100 nm (Fig. 1). They consist of a hydrophobic core that serves as loading space for hydrophobic drugs and an outer shell, or corona, comprised of hydrophilic material that provides a protective interface between the micelle core and external medium. In aqueous media, at copolymer concentrations at or above the critical micelle concentration (CMC), self-assembly results in micelles possessing greater thermodynamic and kinetic stability than that achieved using small-molecule surfactants [7], [8]. Indeed, the copolymers can be tailored to result in stable micelles that are optimized for tumor-selective delivery of therapeutic agents [9], [10], [11]. By formulating small-molecule chemotherapeutics in BCMs, their solubility can be enhanced while their pharmacokinetic, as well as biodistribution profiles, can be favorably altered. Such modulation of the in vivo distribution of small-molecule agents enables a reduction in often dose-limiting normal tissue toxicities and can yield significant improvements in their therapeutic index [12], [13]. Therefore, BCMs provide a functional platform for the design of nano-sized drug delivery systems (NDDSs) to overcome the challenges faced by conventional chemotherapeutics. The chemical diversity of monomers that form the copolymer building blocks offers synthetic versatility enabling customization at the molecular level, and control of the physico-chemical properties of the BCMs (i.e. size, morphology, stability, and surface properties) [14]. The ease of chemical modification of the copolymers also allows for optimization of drug loading (via physical encapsulation or conjugation) and release, as well as surface functionalization with radionuclides and/or targeting moieties (Fig. 1) [15], [16], [17]. Initially regarded as “pharmaceutical curiosities” [2], BCMs presently have the potential to offer three key advantages over conventional formulation strategies: (1) increased solubility of the encapsulated drug [18], (2) high adaptability of the physico-chemical properties of the BCM system [11], [19], and (3) improved biodistribution of drug and thereby reduced systemic toxicity [20].

However, despite intense research activity on NDDSs such as BCMs, and subsequently, an extensive number of publications generated on this topic over the past several decades (Fig. 2), clinical translation has proven challenging. In particular, the achievement of significant improvements in efficacy, characterized by concomitant reductions in tumor burden, disease recurrence and metastatic progression, remains an elusive goal [21], [22], [23], [24], [25]. Today, NDDS-based cancer therapy finds itself at a crossroads, challenging the unique promise and ultimate clinical relevance of nanomedicines [22], [23], [26]. Of note, its disputed state brings into question the future of BCMs, nearly four decades following their emergence as a drug delivery platform. In particular, it has become increasingly evident that the realization of substantial clinical benefits requires clear elucidation of the biological complexity of the drug delivery process and its use as a driving force to guide the development of future nanomedicines. The major challenge remains overcoming the physiological and biophysical barriers imposed by the host, tumor and host–tumor interactions, while integrating due recognition of the vast extent of inter-patient and intra-tumoral heterogeneity [7], [27]. BCMs, in particular, stand out among the advanced NDDSs owing to their potential versatility. Yet, their viability as a successful drug delivery platform relies on the design and implementation of novel approaches that exploit and/or overcome pathophysiological mechanisms.

This review aims to provide a discussion of the attributes and shortcomings of BCM-mediated cancer therapy, particularly within the context of biological barriers and ultimately clinical translation. The design of new and more effective cancer therapy strategies calls for a comprehensive understanding of the underlying pathological mechanisms hindering and/or helping the targeted delivery of BCMs to tumors, the factors driving the success of NDDSs, as well as an awareness of the significant discrepancies observed between pre-clinical and clinical outcomes. First, we aim to provide a review of the key in vivo barriers impeding the effective delivery of chemotherapeutics via BCMs, and present strategies that have been employed in an attempt to overcome these barriers. Finally, the goal of translating BCM technology to the clinic is examined, paying due attention to significant hurdles to its achievement; namely, the design, evaluation and interpretation of in vivo studies. Throughout this review, concepts are illustrated using examples obtained from literature on BCMs. However, in some cases, studies on other NDDSs (e.g. liposomes) are highlighted as a means to enhance our general understanding of the factors that influence the in vivo behavior and performance of these systems.

Section snippets

Biology vs. block copolymer micelles

Effective drug delivery remains an outstanding feat to be achieved, encompassing challenges such as NDDS instability as well as limited tumor accumulation and/or penetration. Further, a third challenge consists of enhancing tumor drug bioavailability, which we describe here as the amount of drug available to tumor cells with the potential to elicit a cytotoxic effect. In this section, our goal is to establish the key in vivo barriers to the effective transport of therapeutics via BCM-mediated

Translatability: best practices and lessons learned

As outlined in the previous section, a number of significant in vivo barriers remain to be overcome for effective anti-cancer drug delivery. Among a variety of nanosystems, BCMs offer a relatively greater degree of control over their physico-chemical characteristics. The question remains whether we can maintain this ‘chemical’ leverage in the face of increasingly complex biological challenges in order to fully exploit this technology, making it a viable treatment option for an increasing number

Conclusions

Today, scientists are presented with a wide array of models and tools at their disposal to assess the performance of nanomedicines. However, an acute awareness and prudence of the capabilities of our pre-clinical models has grown in significance, as we gain a better understanding of those parameters (formulation- or tumor-related) which are most clinically relevant and influential. The ability to design BCMs varying in size, shape and functionalization offers considerable potential to achieve

Acknowledgements

S.E. is funded by the NSERC CREATE Biointerfaces Training Program and holds an Ontario Trillium Scholarship. S.N.E. is the recipient of the Pfizer Canada Graduate Fellowship in Pharmaceutical Sciences and a fellowship from the CIHR Strategic Training Program in Biological Therapeutics. C. A. acknowledges GlaxoSmithKline for an endowed Chair in Pharmaceutics and Drug Delivery and research funding from NSERC (#261514), CIHR (mop-136919), the CIHR Breast Cancer Initiative and the Avon Foundation (

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Editor's Choice 2015”.

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    Equal contributions from both authors.

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