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(1)
(2)
(3)
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Lam, P. C. L. Kwok (eds.), Respirato ryDeliveryofBiologics,NucleicAcids,andVaccines, AAPS
Introductions in the Pharmaceutical Sciences 8
https://doi.org/10.1007/978-3-031-47567-2_4
AntimicrobialPeptidesandProteinsfor
Inhalation
Yuncheng Wang1, Rachel Y. K. Chang1, Warwick J. Britton
2, 3
and Hak-
Kim Chan
1
Advanced Drug Delivery Group, School of Pharmacy, Faculty of Medicine
and Health, University of Sydney, Sydney, NSW, Australia
Centenary Institute and Faculty of Medicine and Health, University of
Sydney, Sydney, NSW, Australia
Department of Clinical Immunology, Royal Prince Alfred Hospital,
Camperdown, NSW, Australia
Hak-KimChan
Email:kim.chan@sydney.edu.au
Abstract
Antimicrobial peptides and proteins (APPs) are gaining attraction as powerful
agents against multidrug-resistant bacteria. The inhalation delivery of APPs
has emerged as a potent tool for treating respiratory infections, given the
ability to achieve high local drug concentrations in the lungs and minimizing
systemic exposure. This chapter reviews recent in vitro and in vivo research
on inhaled APPs, focusing on APP modiication and formulation strategies to
develop stable and inhalable forms of APPs. These strategies include using denantiomers, dendrimers, and prodrugs as APP modiication strategies and
applying new nebulizers, spray drying, and hydrogel techniques as
formulation strategies. Despite the substantial progress in enhancing the
biological activity of APPs, the biological stability of these novel molecules
when aerosolized is yet to be further explored. Similarly, the formulation and
production of inhalable liquid and powder formulations of APPs remain
relatively unexplored. These domains are, however, critical for successful
clinical translation and hence deserve further research efforts.
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Keywords Antimicrobial peptides and proteins (APPs), multidrug-resistant
bacteria – Lung infections – Inhalation therapy
1 IntroductiontoAntimicrobialPeptidesa ndProteins
InhalationTherapy
Antimicrobial peptides and proteins (APPs) in this chapter refer to all the
peptides and proteins possessing direct and/or indirect inhibitory effects
against bacteria. Direct-acting APPs kill bacteria directly, without the need for
other chemicals or systems. By contrast, indirect-acting APPs (host
antimicrobial capacity enhancer APPs), including some subunit
vaccines/antibodies, recombinant cytokines/chemokines, trigger or enhance
other antimicrobial defense responses to kill bacteria. Some APPs have both
direct and indirect antimicrobial effects. For example, host defense peptides
(HDP) are natural peptides that combat bacterial infection though their direct
bactericidal properties and/or by inluencing the host’s immune responses.
Some innate defense regulator (IDR) peptides, which are synthetic and short
peptide analogs of HDPs, can have both direct and indirect antimicrobial
activities [1]. APPs are becoming important therapeutic alternatives due to
the increased number of infections caused by multidrug-resistant (MDR)
bacteria. There are many APPs available or in development pipelines [2], and
several molecules have been approved by the United States Food and Drug
Administration (FDA): colistin, gramicidin D, daptomycin, vancomycin,
oritavancin, dalbavancin, and telavancin [3]. APPs possess many advantages
over conventional antibiotics, including but not limited to, their lower
patterns of resistance, higher antimicrobial activity, and numerous available
options. However, the use of APPs faces several limitations for treating lung
infections. First, systemic therapeutic routes to deliver APPs normally result
in low concentrations in the lung. Second, systemic immune responses to
some APPs may cause toxicity. Third, APPs are generally harder to stabilize
compared with small molecules.
Inhalation therapy, which has been applied in several commercial
antibiotic products, including aztreonam, tobramycin solution, and
tobramycin powder [4], is being considered for the delivery of APPs to
overcome their limitations caused by systemic routes of administration. By
using nebulizers, metered dose inhalers (MDIs), or dry powder inhalers
(DPIs), liquid or dry powder formulations of APPs (natural or modiied) can be
delivered to the lung directly (see Fig. 1) [5]. To generate inhalable aerosols,
the aerodynamic diameter of droplets or particles containing drugs should be
below 5 μm [6].
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Fig.1 Production and delivery of APP inhalable formulations (NPs, nanoparticles)
Inhalation solution and DPI are the two main formulations being studied
for inhalation delivery of APPs. Nebulization has been the primary method for
aerosolization and delivery of APPs into the respiratory tract. Commercial
nebulizers, including air-jet, ultrasonic, and vibrating mesh nebulizers, are
commonly used to deliver inhalation solutions. Air-jet nebulizers use
compressed air to deliver the aerosols [7]. Vibrating mesh nebulizers produce
aerosols by squeezing liquid through a perforated plate that vibrates at a high
frequency (e.g., 100–300 kHz). By comparison, ultrasonic nebulizers exert
ultrasonic waves directly into the liquid to cause a breakup at the liquid
surface to produce the aerosols [8]. Regardless of the type of nebulizers, they
will generate various degrees of stress on the APPs, which may impact the
stability of the biologics. Newer devices, such as the surface acoustic wave
atomizer [9], may also be considered for the delivery of APPs.
Multiple studies have been focused on APPs which are stable and inhalable
in liquid formulations including peptides (TP359 [10, 11], POL7001 [12, 13],
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murepavadin [14, 15], LL-37 [16, 17], SPA4 [18, 19] ST3-H2A2 and IL10R1–7
[20, 21]) and proteins (pyocin S2 [22–24], endolysins [25–28], surfactant
protein (SP)-D [29–31], lagellin [32] and granulocyte-macrophage colonystimulating factor [33, 34]). Moreover, different strategies can be used to
improve the stability and inhalability of these APP inhalation formulations.
To develop more portable and convenient inhalable products, powder
formulation is another option for inhalation drug delivery. Since APPs tend to
be more fragile than small molecules, using dry powder formulation
eliminates the air-liquid interface and mechanical stresses to the biologics
arising from nebulization. However, suitable excipients are necessary to
stabilize the APPs in the dry state. In addition, powder formulations involve
more complex manufacturing equipment, excipients, and physicochemical
characterizations. To date, only a few studies utilized dry powder formulation
technologies for APP inhalation delivery. This chapter will focus on strategies
applied to the formulation of APPs suitable for inhalation.
2 CommercialandOff-LabelInhaledAPPs
2.1 Colistin
Colistin, a cationic polypeptide antibiotic that acts on the bacterial cell
membrane, has been developed as the irst commercial inhalable APP product.
Colistin is commonly used as the last treatment option for MDR bacterial
infections because of its serious side effects. Inhaled colistin can also cause
adverse effects, including cough, bronchoconstriction, and throat irritation.
Thus, its prodrug, colistin methanesulfonate (CMS), was developed, and
released to the market as ColiFin® (Approved in Europe), Promixin
®
(approved in various European Union countries), and Colomycin® (approved
in the UK and Ireland) for inhalation. Various nebulizers, such as the
Respironics I-neb Adaptive Aerosol Delivery system, Aeroneb Go, Pari eFlow
rapid, or Pari LC Sprint nebulizers are used for delivery of CMS [35].
A dry powder formulation of CMS (Colobreathe®, Teva UK Limited) was
also developed [36] and approved for inhalational therapy by the European
Medicines Agency [37]. A CMS dose of 125 mg in each capsule is administered
to patients with the Turbospin delivery device. Another CMS dry powder
formulation containing 25 mg of micronized CMS blended with lactose (60–
103
μm) was approved for compassionate use with Twincer inhaler in
Netherlands [38]. Lactose was used as an excipient as it is FDA-approved and
widely used in inhalation formulations [39].
Diverse animal models, such as mouse, rat, piglet, sheep, and monkey, have
also been extensively explored to study the pharmacokinetics, safety, and
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eficacy of colistin [40–47].
2.2 Vancomycin
Vancomycin, a branched tricyclic glycopeptide isolated from Amycolatopsis
orientalis, has been studied for inhalation delivery in both preclinical and
clinical trials [48, 49]. In another clinical study, nebulized vancomycin
eradicated methicillin-resistant Staphylococcusaureus (MRSA) in 84.3% of
the patients [50]. However, the addition of inhaled vancomycin did not affect
the rates of MRSA eradication at the end of a 28-day oral antibiotic treatment
regimen in a double-blind randomized, placebo-controlled study [51].
Vancomycin dry powder formulation (AeroVanc™) was tested in multiple
clinical trials without disclosing its manufacturing technique. AeroVanc was
found to be well tolerated, and remained above the usual minimum inhibitory
concentration (MIC) values for MRSA for up to 24 h in the sputum [38], and it
signiicantly reduced MRSA sputum density in the subsequent clinical trial
[39]. However, the bacterial killing effect was not promising, which was
probably why a phase 3 study of AeroVanc in CF (cystic ibrosis) patients did
not meet its primary endpoint of improvement in FEV1 (i.e., lung function)
and reduction in pulmonary exacerbations, which made the company halt the
project [40]. Although different clinical trials have shown different eficacy
results, inhaled vancomycin by nebulization of the intravenous formulation
has been applied for off-label use to treat MRSA in CF patients based on its
promising safety proile [51].
3 ClinicalTrialStageProducts
3.1 Lactoferrin
Lactoferrin is an iron-binding glycoprotein with antimicrobial activity. A
phase 1a clinical trial of ALX-009 (a combination of bovine lactoferrin and
hypothiocyanite) tested its safety and tolerability. Based on this safety proile,
CF and bronchiectasis patients have been recruited for a phase 1b clinical trial
to test its eficacy [52]. In a previous study, ALX-009 showed signiicantly
higher antibacterial activity than tobramycin against Pseudomonas
aeruginosa in CF sputum samples [53]. In a P.aeruginosa lung infection model,
delivery of aerosolized lactoferrin (200 μg/mouse) reduced both the
iniltration of leukocytes and pulmonary bacterial load in CF mice.
Furthermore, lactoferrin treatment decreased pulmonary iron levels caused
by CF in mice (iron is essential for P.aeruginosa to develop antibiotic
resistance) [54, 55].
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4 ResearchStageStudies
Apart from colistin and vancomycin (off-label use), most of the APPs are not
available as inhaled therapeutics in the market due to some technical hurdles.
Firstly, APP denaturation and degradation in the sputum and lungs,
particularly in infected patients, are unpredictable prior to the conduct of in
vivo studies. Secondly, APPs are normally more fragile to mechanical stress
compared to small molecules, and this increases the uncertainty in both
formulation and drug delivery. Thirdly, these biologics may trigger immune
responses in humans. Innovative APP modiication and formulation strategies
are investigated and summarized in this section (see Table 1).
Table1 Summary of research studies on inhaled APPs
Strategy APP Formulation Target
bacteria or
disease
Keyindings Reference
Enantiomeric
optimization
WLBU2 Liquid P.aeruginosa Enantiomeric
optimization of
WLBU2 (D8WLBU2) showed
higher stability,
higher
therapeutic
index, and
reduced toxicity
[56]
D8-WLBU2
Dendrimer
synthesis
SET-M33DIM Liquid P.aeruginosa Two-branched
dimeric form of
peptide SETM33 (SETM33DIM) was
resistant to loss
of activity in
biological luids
and maintained
its antimicrobial
activity
[57–59]
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