The effects of polymeric nanostructure shape on drug delivery

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Abstract

Amphiphilic polymeric nanostructures have long been well-recognized as an excellent candidate for drug delivery applications. With the recent advances in the “top-down” and “bottom-up” approaches, development of well-defined polymeric nanostructures of different shapes has been possible. Such a possibility of tailoring the shape of the nanostructures has allowed for the fabrication of model systems with chemically equivalent but topologically different carriers. With these model nanostructures, evaluation of the importance of particle shape in the context of biodistribution, cellular uptake and toxicity has become a major thrust area. Since most of the current polymeric delivery systems are based upon spherical nanostructures, understanding the implications of other shapes will allow for the development of next generation drug delivery vehicles. Herein we will review different approaches to fabricate polymeric nanostructures of various shapes, provide a comprehensive summary on the current understandings of the influence of nanostructures with different shapes on important biological processes in drug delivery, and discuss future perspectives for the development of nanostructures with well-defined shapes for drug delivery.

Introduction

Encapsulation of drugs using polymeric carriers has emerged as the workhorse solution to manage poor biodistribution and stability of bare therapeutics [1]. With the optimized encapsulation technology, therapeutic efficacy can be increased by many folds. Incredible choices in the polymeric designs offer a direct route to optimal carrier design. The physical and chemical attributes of the polymeric carriers play a crucial role in navigating the biological barriers and hence determining the overall success of the therapy. Amongst these attributes, recently the shape of the carrier has been identified as one of the key factors that influence important biological processes, including biodistribution and cellular uptake, in drug delivery applications. The ability to modulate these vital processes via manipulation of carrier shape has opened up new avenues such as engineering of carriers that can evade phagocytosis [2] or development of long-circulating carriers [3]. Realizing the impact of nanostructural shape, in this review we first provide a critical summary of different approaches to fabricate nanostructures with precise shape control, followed by a discussion of the current understanding on the influence of shape on crucial biological aspects of drug delivery.

With the recent advances in synthesis of macromolecules and microfabrication approaches, our capabilities to make nanostructures of different shapes have tremendously increased. Still, there are certain shapes and sizes better accessible than the others via certain methodologies. So, in the first part of this review we will highlight different approaches to make nanostructures of different shapes for drug delivery applications. The discussion of the preparation of nanostructures of different shape will be classified into the top-down and bottom-up approaches. The top-down approaches have opened up the possibilities especially in the sub-micron range, providing access to the range of shapes and also having practically mono-disperse and reproducible nanostructures at will. In the last decade, many methodologies originating from the traditional microfabrication tools have been customized for the preparation of soft nanostructures for biomedical applications. Briefly, in Section 2, the impact of these top-down approaches on the developments of drug delivery vehicles will be presented.

Bioinspired “bottom-up” approaches offer unprecedented advantages as with these methods one can not only reliably assemble but also enable programmed dis-assembly of nanostructures. With a rationally designed amphiphile, a wide range of nanostructures can be readily accessed via facile self-assembly of these amphiphiles. This chemistry-centered approach is relatively simple and cost-efficient, particularly for nanoparticles of sub-100 nm range as it may not have need for any expensive fabrication tools, etc. Core-shell spheres, vesicles and elongated rod-like micelles, some of the reliably and routinely accessed shapes have demonstrated potential to encapsulate a diverse array of therapeutics with high drug loading capacities. In Section 3, apart from highlighting the ‘paradigm-shifting’ works on self-assembly of block copolymers that came along in the last decade or so, we will focus on the recent breakthroughs that we believe will impact the following decades.

Achieving low polydispersity for certain morphologies and similarly, precise presentation of targeting biochemical functionalities via self-assembly approaches have been challenging. To some extent these issues have been addressed by deploying well-defined complex macromolecules of different architectures such as dendrimers and block copolymeric brushes, etc. These classes of sophisticated macromolecules no doubt involve laborious efforts to synthesize. However, the new developments, focused on accelerating and simplifying the synthesis with efficient novel chemistries [4], [5], render these materials worth considering for niche applications, where homogeneity and/or spatial control over ligand presentation are important. In Section 3.2, we will highlight the latest developments in this molecular approach.

With the synthetic access to numerous nanostructures of different shapes, it is prudent to appreciate the roles of particle shape on various biological aspects involved in drug delivery for the development of carriers optimized for specific biomedical applications. As will be seen in this review, differently shaped particles exhibit vastly different pharmacokinetic properties and propensity for phagocytic or endocytic uptake, which may greatly influence their success as drug delivery vehicles. The emergence of several reports demonstrating the superior in vivo anti-tumor effects of drug-loaded biodegradable and non-traditionally shaped carriers such as filamentous micelles [3], [6] and polyester dendrimer-poly(ethylene oxide) hybrid [7], for instance, has undoubtedly highlighted the immense potential of particle shape modulations in improving the overall drug delivery outcome. As such, in Section 4, we will provide a comprehensive overview of recent studies that probe the role of particle shape on various drug delivery aspects including biodistribution, cellular internalization and cytotoxicity. Finally in the outlook, Section 5, we will identify key areas wherein we believe that more work needs to be done so that as a community, we can understand the role of nanostructural shape and capitalize on their biological effects to develop practical and effective carriers for optimized drug delivery.

Section snippets

Top-down approach

Fabrication techniques typically reserved for microelectronics devices have been employed for the generation of nanoparticles of complex three dimensional nanostructures, of defined size and shape. These techniques are generally referred to as “top down” approaches and recent advances in this area have produced nanostructured materials that have dimensions that approach self-assembly methodologies. Ability to exert precise control over numerous critical nanoparticle parameters, ease of

Self-assembly

Contrast to ‘top-down’ approaches highlighted in Section 2, ‘bottom-up’ approaches primarily rely on non-covalent interactions for the self-assembly of the constituent (macro) molecules, without any or minimal external intervention, for the formation of ordered aggregates [39]. Hence this approach is cost effective, without any need for huge initial investment on microfabrication tools, and energy efficient owing to the spontaneity of the process and mild processing conditions. Molecular

Influence of shape on biological processes

Although extensive work using spherical particles has yielded many valuable insights on the contributions of particle parameters such as size and surface chemistries to biological processes, information on the biological influence exerted by particle shape are relatively lacking [207]. In recent years, emerging evidence from a limited number of in vivo studies comparing shape effects of synthetic structures (Table 1) have highlighted discrepancies in biological behaviors between conventional

Conclusion and future outlook

Particle shape is a long-neglected geometric parameter in the characterization and application of nanoparticles for drug delivery. In the past decade, however, tremendous progress made in the various synthetic methodologies, such as the top-down and bottom-up approaches, for attaining diversely shaped particles, has gradually paved the way for the evaluation of the effects of particle shape on various biological processes important in drug delivery. As can be seen in this review, emerging

Acknowledgments

This work was funded by the Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research, Singapore.

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