Polymer-drug conjugates as inhalable drug delivery systems: A review
Introduction
Polymers and polymer-based drug delivery systems have undergone an enormous expansion in the past decade, with the clinical and pre-clinical development of polymer-based nanomedicines and other biomedical applications. The key feature of a polymer-drug conjugate is that rather than containing a drug that is non-covalently encapsulating within a polymeric structure, the drug is physically conjugated to the polymeric carrier [1]. In this regard, problems associated with ‘burst’ and/or uncontrolled drug release can be largely overcome and the drug can be covalently linked to the polymer via linkages that are specifically designed to liberate drug within certain structures, or at a predicted rate in vivo.
The concept of polymer-drug conjugates was first introduced by Helmut Ringsdorf in 1975 [2]. According to this concept, an ideal polymer-drug conjugate is characterised by a hydrophilic polymer backbone as a vehicle and a bioactive agent(s) that is usually bound to the polymeric scaffold via a biological response linker. Sometimes a targeting moiety or a solubility enhancer may also be introduced into the conjugate to improve pharmacokinetic behaviour and therapeutic efficiency (Fig. 1) [2], [3•]. In general, polymer-drug conjugates offer several advantages as drug delivery moieties, including 1) the capability to achieve high drug payloads, 2) improved drug solubility, 3) modulation of drug pharmacokinetics (including prolonged plasma exposure and optimised biodistribution behaviour, resulting in enhanced therapeutic efficacy), 4) reduced systemic and local side-effects as a result of highly irritant or cytotoxic drugs, 5) enhanced in vivo drug stability, and 6) controlled rate and site of drug liberation. Despite these advantages, the full potential of polymer-drug conjugates as drug delivery platforms has yet to be fully harnessed, since the majority of current ‘nanomedicinal’ drug delivery systems still utilise the cheaper drug encapsulation approach.
Polymer-drug conjugates are often synthesised using one of three strategies, including 1) conjugating the drug to an established polymer, 2) conjugating the drug to a monomer, followed by reversible addition fragmentation transfer (RAFT) polymerisation, ring-opening metathesis polymerisation (ROMP) or ring opening polymerisation (ROP), and 3) using an existing drug containing two or more functional groups as a monomer for poly-drug Polymerisation [4], [5]. The first strategy can lead to poor control over drug conjugation and limited drug loading, depending on the size and nature of the polymer structure. However, polymerisation of drug-monomer conjugates generally provides good control over drug loading and the final product [5], [6]. Drugs are often conjugated to the polymers via biodegradable linkers which can control the site and rate of drug liberation, although the linker has to be carefully selected to display optimal in vivo drug release rates for the intended therapeutic application [7]. It is important to note however, that the physicochemical properties of the polymer can have an impact on the in vivo liberation of drugs linked via ‘biodegradable’ linkers, particularly when access by an enzyme is required [1], [8], [9].
One of the most significant advantages that polymer-drug conjugates have, as alluded to above, is the ability to change the pharmacokinetic and biodistribution behaviour of the loaded drug [1]. In this regard, polymer-drug conjugates have traditionally been administered exclusively via the intravenous route as a result of their size and general hydrophilic nature limiting absorption after oral administration [3]. Subcutaneous or intramuscular delivery also provides a means to access the blood using a less invasive approach, but bioavailability can be limited in some cases. However, recent interest by big Pharma in non-invasive drug delivery approaches and targeted delivery to the lungs to improve the treatment of lung-resident illnesses that are traditionally treated with oral medications, has sparked a tremendous worldwide interest in the inhaled delivery of nanomedicines.
The pulmonary route possesses several distinct advantages over conventional oral or injectable routes of administration, including lower enzymatic activity in the lungs than that found in the gut, the avoidance of first-pass metabolism as well as the thin alveolar membrane, high surface area for absorption and extensive vasculature that can facilitate the rapid systemic absorption of drugs after inhaled administration [10], [11]. However, despite the potential for very rapid drug absorption from the lungs for relatively low molecular weight materials (several thousand Da max), the tight intercellular junctions between alveolar cells typically limits the passage and systemic access of larger constructs, such as polymers. This has the effect of slowing the systemic absorption of polymers and providing the opportunity for sustained lung exposure to polymer-drug conjugates (and therefore to the drug). This is particularly advantageous when treating lung-resident illnesses, since the exposure of key disease-mediating cells to the drugs can be significantly increased when compared to oral drug administration, and systemic exposure (and therefore related side effects) can be reduced. It also means that lung clearance mechanisms other than systemic absorption must play a more significant role in removing the polymer from the lungs [12], [13]. To date however, there is limited knowledge about the contribution of each lung clearance pathway in the removal of inhaled polymers and nanoparticles from the lungs [14••], [15], which is important for clinical translation and regulatory approval. Moreover, the majority of studies investigating the fate of inhaled nanomaterials have been based on examining the lung clearance kinetics of the drug, rather than the polymer or polymer-drug conjugate. The critical issue here is that the safety of inhaled polymer-drug conjugates has also been called into question, based on widespread literature suggesting that nanomaterials, albeit non-biodegradable/non-biocompatible nanoparticles, are ‘toxic’ in the lungs [16], [17], [18], [19], [20]. It is therefore important to understand the rate and mechanisms of polymer clearance from the lungs in order to design optimal dosing schedules that limit the long term retention of the polymer in the lungs and the potential for local adverse effects.
In the present review, we therefore provide a comprehensive overview of the state-of-the-art for inhalable polymer-drug conjugates (Fig. 2) and have summarised the critical in vivo literature in Table 1. An additional focus of this review is to detail our current understanding of the in vivo behaviour and safety of inhaled polymer-drug conjugates. Finally, the need for further research and development of polymer-drug conjugates is also discussed with an emphasis on current knowledge gaps and future perspectives.
Section snippets
Linear PEG-drug conjugates
PEG is a polyether containing repeating units of ethylene glycol (Fig. 2A). It is highly biocompatible, non-immunogenic, highly water soluble and FDA approved for use in medicine and other biomedical applications [35]. PEG exists as either linear or branched chains. Linear PEG is most commonly used as a drug carrier or surface coating on nanoparticles to improve biocompatibility and/or solubility, and conjugation processes are generally very straight forward [36], [37], [38•]. In general, due
Dendrimer-drug conjugates
Dendrimers are fundamentally hyperbranched polymers, but contain a more well-defined scaffold structure. Specifically, dendrimers are constructed in a radial manner from monomers that contain at least 3 functional groups (with 2 functional groups being identical to build the branched structure). They contain three major domains 1) a central core on which the polymer scaffold is built, 2) the scaffold which is formed through a series of additions of layers or ‘generations’ of monomers, and 3)
Polyethyleneimine (PEI)-drug conjugates
PEI has been successfully used as an inhalable non-viral gene and drug delivery vector [28•], [61], [62]. Linear PEI contains repeating units of secondary amine-(NH) and aliphatic groups (-CH2-CH2-) (Fig. 2D), while branched PEI contains primary, secondary and tertiary amines [63]. PEI has high transfection efficiency due to its high density of cationic amine functional groups that condense negatively charged DNA and RNA via electrostatic interactions [64], [65]. PEI can also interact with
Chitosan-drug conjugates
Chitosan is considered to be a popular ‘potential’ inhalable delivery system and nanoparticle coating as a result of its capability to deliver drugs locally and systemically via mucosal routes [70], [71]. It is both biocompatible and biodegradable and is an FDA approved polymer for wound dressings [72]. Chitosan contains linear polysaccharides that are derived from chitin which is composed of d-glucosamine and N-acetyl-d-glucosamine (Fig. 2E) [71]. The polymer is cationic in nature due to the
Hyaluronic acid-drug conjugates
Hyaluronic acid (HA) is a naturally occurring biopolymer composed of repeating disaccharides units of N-acetylglucosamine and d-glucuronic acid (Fig. 2F) [83]. The pKa of the carboxylic group of HA is between 3 and 4 and thus at physiological pH, HA exists as a polyanion. HA can adsorb significant amounts of water and expand up to 1000-times compared to its original solid volume, thereby forming hydrogels [84]. They are predominantly found in the extracellular matrix of connective tissues and
Other polymers
With the exception of the above mentioned polymers that are more commonly evaluated as inhalable drug carrier systems, several other polymers have also been evaluated as inhalable drug vectors. Carbopol® for instance, is a high molecular weight polyacrylic acid-based crosslinked mucoadhesive polymer that typically contains repeating carboxyvinyl units. Carbopol® is commonly used in oral tablets and mucosal formulations. In a recent study though, Carbopol was conjugated to wheat germ agglutinin
In vitro observations
To date, much of the literature surrounding the pulmonary toxicity of inhaled ‘nanomaterials’ has been based on non-biodegradable structures, such as carbon or metals. Very little work has been conducted on understanding the complex pulmonary toxicology of relatively biocompatible and biodegradable polymers, and much of the existing literature has been based on in vitro evaluations, or on the in vivo lung administration of polymer-drug conjugates containing cytotoxic drugs [22], [27], [28•],
Current opinion and future trend on polymer-drug conjugates
Polymer-drug conjugates have enormous potential as an inhalable drug delivery platforms for the treatment of lung diseases. They also have some potential as systemic delivery systems using the inhaled route as an alternative to more invasive injectable routes of delivery. They have several chemical and structural attributes which can be tailored to modulate drug release kinetics, cellular and subcellular interactions within the lungs and lung clearance pathways. Although a large number of
Acknowledgements
LMK is supported by an NHMRC Career Development Fellowship.
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