The challenges facing block copolymer micelles for cancer therapy: In vivo barriers and clinical translation☆
Graphical abstract
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 (
References (167)
- et al.
Polymerized micelles and their use as adjuvants in immunology
J. Pharm. Sci.
(1976) Nanoparticles — a historical perspective
Int. J. Pharm.
(2007)- et al.
Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials
Colloids Surf. B
(1999) - et al.
Progress of drug-loaded polymeric micelles into clinical studies
J. Control. Release
(2014) - et al.
Block copolymer micelles for delivery of cancer therapy: transport at the whole body, tissue and cellular levels
J. Control. Release
(2009) - et al.
Polymeric micelle stability
Nano Today
(2012) - et al.
Block-copolymer micelles as long-circulating drug vehicles
Adv. Drug Deliv. Rev.
(1995) - et al.
Nano-engineering block copolymer aggregates for drug delivery
Colloids Surf. B
(1999) - et al.
Polymeric micelles — a new generation of colloidal drug carriers
Eur. J. Pharm. Biopharm.
(1999) Physical stimuli-responsive polymeric micelles for anti-cancer drug delivery
Prog. Polym. Sci.
(2007)
Micellization of cisplatin (NC-6004) reduces its ototoxicity in guinea pigs
J. Control. Release
SMART drug delivery systems: back to the future vs. clinical reality
Int. J. Pharm.
Nanosystem drug targeting: facing up to complex realities
J. Control. Release
Towards more effective advanced drug delivery systems
Int. J. Pharm.
Drug targeting to tumors: principles, pitfalls and (pre-) clinical progress
J. Control. Release
Influence of molecular weight on passive tumour accumulation of a soluble macromolecular drug carrier
Eur. J. Cancer
The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect
Adv. Drug Deliv. Rev.
An investigation of the filtration capacity and the fate of large filtered sterically-stabilized microspheres in rat spleen
Biochim. Biophys. Acta
Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles
Int. J. Pharm.
Therapeutic synthetic polymers: a game of Russian roulette?
Drug Discov. Today
Long-circulating poly(ethylene glycol)-poly(D,L-lactide) block copolymer micelles with modulated surface charge
J. Control. Release
Influence of formulation variables on the biodistribution of multifunctional block copolymer micelles
J. Control. Release
Image-based analysis of the size- and time-dependent penetration of polymeric micelles in multicellular tumor spheroids and tumor xenografts
Int. J. Pharm.
Development of the polymer micelle carrier system for doxorubicin
J. Control. Release
Development of copolymers of poly(D, L-lactide) and methoxypolyethylene glycol as micellar carriers of paclitaxel
Colloids Surf. B
Biodegradable hybrid polymer micelles for combination drug therapy in ovarian cancer
J. Control. Release
Vessel abnormalization: another hallmark of cancer? Molecular mechanisms and therapeutic implications
Curr. Opin. Genet. Dev.
Cellular abnormalities of blood vessels as targets in cancer
Curr. Opin. Genet. Dev.
Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors
Am. J. Pathol.
Role of tumor vascular architecture in drug delivery
Adv. Drug Deliv. Rev.
Anticancer nanomedicine and tumor vascular permeability; where is the missing link?
J. Control. Release
Enhanced tumor accumulation and prolonged circulation times of micelle-forming poly(ethylene oxide-aspartate) block copolymer-adriamycin conjugates
J. Control. Release
Rate of biodistribution of STEALTH((R)) liposomes to tumor and skin: influence of liposome diameter and implications for toxicity and therapeutic activity
BBA Biomembranes
EPR: evidence and fallacy
J. Control. Release
Does a targeting ligand influence nanoparticle tumor localization or uptake?
Trends Biotechnol.
Targeting nanoparticles to cancer
Pharmacol. Res.
APN/CD13-targeting as a strategy to alter the tumor accumulation of liposomes
J. Control. Release
In vivo tumor targeting by a NGR-decorated micelle of a recombinant diblock copolypeptide
J. Control. Release
Assessment of target enrichment platforms using massively parallel sequencing for the mutation detection for congenital muscular dystrophy
J. Mol. Diagn.
Aberrant vascular architecture in tumors and its importance in drug-based therapies
Drug Discov. Today
Watersoluble polymers in medicine
Angew. Makromol. Chem.
The drug discovery by nanomedicine and its clinical experience
Jpn. J. Clin. Oncol.
Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size
Nat. Nanotechnol.
Improving drug potency and efficacy by nanocarrier-mediated subcellular targeting
Sci. Transl. Med.
Micellar nanocarriers: pharmaceutical perspectives
Pharm. Res.
Nanoparticles in medicine: therapeutic applications and developments
Clin. Pharmacol. Ther.
Design, functionalization strategies and biomedical applications of targeted biodegradable/biocompatible polymer-based nanocarriers for drug delivery
Chem. Soc. Rev.
Poly(ethylene glycol)-b-poly(epsilon-caprolactone) micelles containing chemically conjugated and physically entrapped docetaxel: synthesis, characterization, and the influence of the drug on micelle morphology
Biomacromolecules
Bundled assembly of helical nanostructures in polymeric micelles loaded with platinum drugs enhancing therapeutic efficiency against pancreatic tumor
ACS Nano
Facing the truth about nanotechnology in drug delivery
ACS Nano
Cited by (0)
- ☆
This review is part of the Advanced Drug Delivery Reviews theme issue on “Editor's Choice 2015”.
- 1
Equal contributions from both authors.