Designing peptide nanoparticles for efficient brain delivery

Introduction

To successfully deliver its cargo to a target tissue, a nanocarrier must navigate through the body while eliciting minimal immunogenic response and avoiding off-target delivery of cytotoxic compounds. In brain delivery, this challenge is often magnified by the need to achieve transport across the blood–brain barrier (BBB), perhaps the most tightly regulated biological barrier in the human body. Essential to success in this area are novel approaches and materials that combine complex functionality with biocompatibility. However, these two properties are often compromised as complex functions require access to untested chemistries that can be potentially toxic. Avoidance of toxicity is particularly critical in developing systems for the treatment of central nervous system (CNS) disorders, which adds an extra dimension to the toxicological profile: the neurological one. One way around this is to use the same chemical currency as nature and adapt, functionalise, and synthesise it to make intrinsically safe materials. Among these, polypeptides are the most versatile and indeed combine almost unlimited functionality with biocompatibility and biodegradation.

Synthetic polypeptide materials have largely proven their suitability in drug and gene delivery with overwhelming examples in the literature and a number of successful products in clinical trials or market stage [1]. Although still less exploited in the treatment of CNS disorders, a growing body of work shows that nanomaterials based on amino acid building blocks have significant promise in brain delivery. Evidence of this is the first polymeric drug reaching the market, Copaxone® (glatiramer acetate from Teva Pharmaceutical Industries Ltd.). This random copolymer, which consists of L-alanine, L-lysine, L-glutamic acid and L-tyrosine, is Food and Drug Administration (FDA)-approved for the treatment of relapsing–remitting multiple sclerosis and has been among the top 10 selling drugs worldwide [[2], [3], [4], [5], [6]]. Another promising candidate is OpaxioTM (paclitaxel polyglumex from CTI Biopharma), a P(Glu)-paclitaxel conjugate which is in phase III clinical trials for the treatment of several different cancers. Of note, OpaxioTM was designated as an orphan drug for glioblastoma (GBM) treatment in combination with radiotherapy [[7], [8], [9]].

In this review, we focus on the design of peptide nanoparticles for the delivery of therapeutics into the brain, focussing chiefly on delivery via the BBB. We summarise representative examples of polypeptide-based nanocarriers in the preclinical stage applied in the delivery of therapeutics and imaging agents to the brain. We then identify the different strategies followed to cross the BBB, as well as identifying alternative methods to achieve delivery of NPs to the brain. We first discuss the molecular engineering of nanocarriers, including synthetic pathways by which one can make and functionalise peptides (Section 2), and the supramolecular rules to control peptide self-assembly (Section 3). In the latter section, we argue that traditional, top-down design may not be the best approach to producing engineered peptide nanostructures. Instead, evolutionary methods, both in silico and experimental, might prove more fruitful. The majority of the review focuses on the BBB structure and the mechanisms of transport that facilitate the entry of peptides and proteins across the BBB and into the brain (Section 4). Given the challenges involved in engineering NPs that can cross the BBB, we then look at alternative pathways for brain delivery, including localised, convection-enhanced, and intranasal administration (Section 5). Finally, we discuss the alterations to the BBB that occur due to pathological conditions such as stroke, which both pose challenges and provide opportunities in engineering NPs for brain delivery (Section 6).

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Section snippets

Synthetic pathways to produce and functionalise peptide nanoparticles for brain delivery

Peptide NPs are typically formed from the self-assembly of either polypeptide-bearing amphiphilic block-copolymers or peptide amphiphiles (PAs) [10]. Although not always required, peptide NPs often benefit from being functionalised with ligands that target specific receptors expressed, for example, at the surface of brain endothelial cells (BECs) or the nasal epithelium [11]. This strategy introduces additional complexity in terms of design and chemical control that complicates the

Peptide self-assembly

Controllably producing peptide nanostructures requires us to predict secondary and tertiary structure from amino acid sequence and the subsequent self-assembly behaviour of the polypeptide. The first of these is a major open problem in molecular biology [58], while the second is a major open problem in physical chemistry [59]. As such, most peptide self-assembly work still relies on rules of thumb developed for polymer self-assembly. However, the rich array of interactions between peptides,

Transport to and across the BBB

Negotiating the biological barriers that regulate transport of molecules through the body and into the brain is one of the biggest open problems in drug delivery today. The CNS functions are maintained by the meticulous coordination of the activity of multiple cells within a neurovascular unit (NVU), including vascular cells (endothelial cells, pericytes, and smooth muscle cells), glia (astrocytes, oligodendrocytes, and microglia) and neurons [[144], [145], [146]]. Within the NVU, the

Alternative administration routes to the brain

Rather than engineering peptide NPs to cross the BBB, it may be easier to reach the brain by means of a different administration route. The strategies summarised in this section may or may not rely on the use of ligands and include localised administration via intracerebroventricular (ICV), intrathecal (IT) or stereotactic injection directly into tumours; convection-enhanced delivery (CED) and intranasal administration (IN). These strategies have a number of benefits and disadvantages: IN

Targeting the BBB in pathological conditions

In most of the examples described above, the design of the peptide NPs was based on the physiology of a healthy BBB and thus overlooks the significant effects of brain disorders on integrity of the barrier and transport across the BECs [144,292]. Indeed, reductions in the cerebral blood flow (CBF), microvascular pathologies, aberrant angiogenesis, breakdown of the BBB due to disruption of the TJs, and altered transport systems in BECs, almost certainly affect the fate of peptide nanocarriers.

In

Conclusions and future outlook

There is an unquestionable increase in the prevalence of brain disorders, including brain tumours, PD, and AD. This trend will almost certainly continue due to an ageing population, generating a major problem in healthcare systems across the world. While many efforts have been made in the field to improve current therapies and develop new disease-modifying therapies, there is a clear need for further investment. The treatment of brain disorders is particularly challenging due to (i) the

Acknowledgments

GB thanks the ERC for the starting grant (MEViC 278793) and Consolidator Award (CheSSTaG 769798), the EPSRC/BTG Healthcare Partnership (EP/I001697/1), EPSRC Established Career Fellowship (EP/N026322/1), EPSRC/SomaNautix Healthcare Partnership EP/R024723/1, CRUK City of London Centre for a multidiscipilnary reserch proejct, and Children with Cancer UK for the research project (16-227). ADC is supported by the Marie Skłodowska-Curie Actions for an Individual European Fellowship.

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These authors contributed equally.

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