Challenges facing colloidal delivery systems: From synthesis to the clinic

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Abstract

Improving therapeutic delivery to the body will have significant benefits for the treatment of a variety of diseases. Incorporating drugs inside engineered colloidal carriers is a promising approach that can lead to improved drug delivery. Such carriers offer a number of advantages, as they can protect therapeutic cargo from degradation by the body, limit potentially harmful side effects of the drug, and also allow targeted drug delivery to the desired site of action. Colloidal carriers have the potential to enable clinical use of a number of therapeutics, such as siRNA and peptides, which if administered in their naked form can degrade before demonstrating a viable therapeutic effect. A number of challenges, such as efficient therapeutic loading into the carrier, targeted and specific delivery in the body whilst evading biological defence mechanisms, and controlled release of therapeutically active cargo, must be met for these systems to be clinically relevant. In this review, we focus on recent advances and some of the pertinent challenges faced in developing clinically relevant colloidal drug carriers. We primarily focus on self-assembled carriers such as liposomes, polymer micelles and polymersomes, and carriers prepared through templated-assembly, for example, layer-by-layer assembled capsules and PRINT (particle replication in non-wetting templates) particles.

Graphic Abstract

Research Highlights

► Recent advances in the development of colloidal drug delivery systems. ► Mechanisms that release drugs in response to biological stimuli. ► Factors that affect the biodistribution of colloids. ► Targeting delivery vehicles to specific areas in the body. ► Mechanisms for the internalisation of particles into cells.

Introduction

Recent advances in the assembly of responsive, nanoengineered colloidal carriers have shown potential for improving drug delivery for a range of diseases [1], [2], [3]. Current treatments for diseases such as cancer are limited by the harmful side effects of chemotherapy drugs before they reach the site of action. Developments in vaccine and gene therapy are also challenging due to degradation of sensitive cargo such as DNA, RNA or peptides. Thus, the incorporation of drugs into nanoengineered carriers has the potential to dramatically improve treatment options by protecting the cargo from degradation in vivo, limiting any potential harmful side effects and targeting the therapeutic directly to the site of action.

However, certain critical challenges must be met when developing drug delivery systems, including: efficient therapeutic loading into the carrier; targeted and specific delivery in the body whilst evading biological defence mechanisms; and controlled release of therapeutically active cargo. The development of a range of self-assembled delivery systems offers the potential to achieve these goals by careful design and assembly of the molecular building blocks. In this review, we highlight some of the recent developments in the assembly of nanoengineered colloidal drug carriers, drug loading and release from these carriers, and their application in vitro and in vivo. We focus on colloidal carriers that have shown promise in clinical studies (e.g., liposomes, polymer micelles and polymer particles), and emerging carriers such as polymersomes and those prepared from templated-assembly (layer-by-layer (LbL) capsules and PRINT (particle replication in non-wetting templates) particles). We also present some systems that are larger than the colloidal size regime (>1 µm), however, the techniques used in their assembly can readily afford submicron-sized delivery systems. Hence, these systems can provide important insights that may be exploited and applied in the preparation of carriers in the colloidal domain.

Section snippets

Particle assembly/formation

A variety of self-assembly techniques have been employed to synthesise particles of different sizes, shapes, compositions and different degradation properties. In this review, we focus on self-assembled systems that rely on either the spontaneous ordering of molecules into engineered structures (polymer complexes, liposomes, micelles, and polymersomes) or the templated-assembly of LbL capsules and PRINT particles (Fig. 1) [4], [5], [6]. Other colloidal carriers, such as metal/inorganic

Loading and release mechanisms

For a delivery system to have therapeutic relevance, it is fundamental that the material allows effective loading and release of cargo, such as anticancer drugs, DNA or proteins. Many of the therapeutics investigated for loading within delivery systems are either toxic to healthy cells or extremely fragile. Therefore, the delivery system should ideally release only at specific targeted sites to optimise the therapeutic outcomes. The controlled loading and release in many colloidal delivery

Biodistribution

One of the major challenges faced by drug carriers is their rapid clearance by the natural defence mechanisms of the body. Clearance by white blood cells, the mononuclear phagocytic system (MPS) (also known as the reticuloendothelial system, RES), and the renal system play a major role in the efficacy of colloidal delivery systems [80]. Typically, colloidal drug carriers are administered to the body through intravenous injection to achieve quick distribution of the particles throughout the body

Targeting

To optimise the delivery of therapeutics to specific areas in the body, two distinct strategies have been employed: passive targeting, which exploits the Enhanced Permeability and Retention (EPR) effect of many tumours [99]; and active targeting, which relies on the binding of the particles to specific receptors on the surface of certain cells.

The EPR effect has been extensively used in a number of particle delivery systems to concentrate drugs within tumours. Particles naturally accumulate in

Cellular internalisation and fate

The therapeutic effect of most drugs occurs in specific locations within the cell, so the intracellular fate of the drug is vital. Therefore, it is important to understand the mechanisms involved in internalisation of the delivery systems, as they play a significant role in the intracellular trafficking and chemical environment that the therapeutic cargo is exposed to. Hydrophobic, low molecular weight compounds can passively diffuse across the lipid membrane, while other compounds can enter

Conclusions

There has been considerable progress in the development of engineered colloidal drug carriers over the last 5 to 10 years. In particular, a number of intelligent loading and release mechanisms have demonstrated potential in in vitro studies. Nevertheless, challenges still remain. The most pressing challenge is to evade the body's natural foreign defence mechanisms to allow long blood circulation times. Shape and PEGylation have been demonstrated to significantly improve the blood circulation

Acknowledgements

This work was supported by the Australian Research Council under the Federation Fellowship, Discovery Project and Postdoctoral Fellowship schemes, and by the National Health and Medical Research Council under the Program Grant 487922. We thank Dr Yan Yan, Dr Hannah Lomas and Marc Riemer for the critical reading of the manuscript.

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