Protein and peptide delivery to lungs by using advanced ...

Introduction

Lungs serve as a vital target for drug delivery since the past several decades. Not only do they provide the quickest access to treat localized respiratory diseases, but also offer a large surface area for the systemic absorption of deliberated drugs [1]. As one of the main interfaces between the organism and the environment, the pulmonary system has evolved into a sophisticated defense system [2]. This defense system is largely responsible for clearing any offending agents from entering the respiratory tract and is tightly regulated to reduce inflammation that could impair gas exchange in the organism [3,4]. From a drug delivery and targeting perspective, these components serve as barriers that impede an efficient drug delivery and absorption of cargo dugs in the pulmonary tract. Reported studies on the anatomy of the lungs have shown that few distinct structures of the lungs aid in drug delivery. There are four types of cells that are present in the alveolar region of the lungs, including the alveolar macrophages, epithelial type I and II cells and the alveolar brush cells (type III) [2]. The alveolar type I cells have a large cytoplasmic volume and exhibit only sparse cellular organelles, which are morphometric features that enhance drug transport to the lungs [5]. The respiratory airway and alveolar lining fluids contain at least one layer of an endogenous lung surfactant that extends its fatty acid tails into the air space [6]. Multiple studies have reported several interactions between lung surfactants and inhaled drugs. For example, the solubility of glucocorticosteroids enhanced upon interacting with lung surfactants, which could possibly affect the residence time of these steroid molecules in the lungs [7]. Moreover, strong interactions between the polypeptides, ditirelix and cyclosporin A and the lung surfactants, which suggests their limited absorption from the lungs, hence leading to a prolonged retention time of the drugs in the lungs [8].

The lungs play an important role in drug delivery, especially in the distribution and accumulation of compounds [9]. Reportedly, the predominant mechanism of distribution into the lungs is by simple diffusion followed by partitioning into membranes and subcellular organelles [10,11]. The rate and extent of lung uptake largely depends on the physicochemical properties of the cargo drug, which includes lipophilicity, degree of ionization and the affinity of the drug to plasma proteins and tissue macromolecules [12]. Hence, a vast number of drugs possess an innate property to deposit to the lungs otherwise; the rational modifications lead to the achievement of pulmonary delivery (Fig. 1).

Pulmonary delivery offers several advantages over systemic delivery in the treatment of respiratory and systemic diseases. The pulmonary drug delivery systems deliver higher concentrations of a drug directly to the disease site for the treatment of respiratory disorders. This minimizes the systemic side effects and offer a rapid clinical response. In addition, it attains a similar or superior therapeutic effect at a fraction of the systemic dose. Moreover, it can bypass the classic barriers to achieve a superior therapeutic efficacy compared to the other routes of administration, such as the gastrointestinal (GI) absorption and first-pass metabolism in the liver [1]. Furthermore, for an effective treatment of systemic diseases, the pulmonary route offers a non-invasive ‘needle-free’ option. It is also suitable for delivering a broad range of drugs from small molecules to large proteins [13,14]. Moreover, the slow mucociliary clearance in the lungs results in prolonged residency of the deliberated drug in the lung. Lastly, drug delivery to the lungs is independent of extracellular enzymes, dietary complications and interpatient metabolic differences that affect GI absorption [14].

Despite the potential benefits of protein and peptide delivery to the lungs, there are several challenges that impede an optimum efficacy. As such, an aerodynamic diameter between 1 and 3 μm ensures an efficient delivery of the cargo drug molecules to the lungs as inhaled microparticles. Advancements in the design of inhaled particles and their respective devices over the past decades resulted in highly reliable delivery of the therapeutic aerosol with lung depositions reaching up to 60% [15,16]. Furthermore, the lung epithelia poses a crucial barrier to absorption of inhaled drugs and proteins. It has a thickness of 50–60 μm in the trachea, which further reduces to an extremely thin 0.2 μm in the alveoli. However, the present day delivery systems have become relatively effective in delivering the cargo drugs into the lungs, irrespective of the different epithelial surfaces [17].

This review primarily focuses on discussing the current trends and advancements in the delivery of protein and peptides to the lungs using advanced drug delivery methods. Vulnerability to the digestive enzymes in GI tract makes the oral delivery of peptides and proteins quite challenging. Moreover, intranasal, and transdermal administration of such compounds are largely hindered due to their large particle size that prevents them from naturally permeating the skin or nasal membrane. Thus, for many years, the major routes of administration for proteins have been the intravenous or intramuscular routes. However, since the successful delivery of insulin to the lungs in 1925 [13], the pulmonary route has been of much interest in protein and peptide drug delivery.

The systemic delivery of therapeutic proteins and peptides through inhalation-based techniques present one of the emerging applications of pulmonary drug delivery. In comparison to other non-invasive methods of administration, the deeper tissues of the lungs provide a higher bioavailability for proteins through inhalation [17]. As such, in contrast to subcutaneous injections, insulin from the lungs is more quickly absorbed and cleared, which makes insulin dosing and coordination with meals easier for patients. Even though the inhaled peptides to treat systemic diseases are not commercially available, however, there are several peptide and protein based formulations currently in the different phases of clinical trials.

Inhaled medication has been available for the treatment of lung diseases for several decades. It presents an optimal route of administration of the first-line therapy for asthma, cystic fibrosis, chronic bronchitis, and chronic obstructive pulmonary diseases. Reportedly, the pulmonary delivery also served as a potential route for the treatment of systemic diseases, such as diabetes mellitus. This review provides insights on the potential of therapeutic proteins and peptides delivered to the lungs for an effective management of respiratory disorders and systemic diseases.

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Section snippets

Nanosystems for the delivery of protein and peptide biologics to the lung tissues

Protein and peptide delivery (PPD) has attracted a great deal of interest in the last two decades owing to their application in the biomedical and healthcare fields (Fig. 2). Current applications of PPD encompasses targeted treatment of pulmonary arterial hypertension, cystic fibrosis, Chronic Obstructive Pulmonary Disease (COPD) and lung cancer. Iloprost, a newly designed prostacyclin analogue finds utility in the treatment of asthma due to its pulmonary selectivity and minimal adverse

Physiological proteins for mitigating pulmonary diseases

A suitable pulmonary tissue plasminogen activator (tPA) formulation as a nebulizer maintains protein stability, fibrinolytic and biologic activities. This formulation supports the treatment of acute lung respiratory distress syndrome (ARDS) by employing a targeted pulmonary delivery of the therapeutic protein to the lungs [33]. Intratracheal dose of nebulized pulmonary formulation of tPA further assists in the treatment of ARDS and administration of pf-tPA did not result in any detectable

Nucleic acids-based formulations to maintain an optimal respiratory health

In 2013, a team of researchers published a study on the delivery of the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) in recombinant adeno-associated virus (rAAV) to lung cancer models of mice through inhalation. It successfully reduced tumor progression in mice. Hence, it is suggested that aerosol delivery of the 4E-BP1 gene to the lungs with the aid of rAAV as a carrier may be useful in treating lung cancer [67]. Another study reported that electroporation

Enzyme-based protein formulations for managing inflammatory conditions

An investigation conducted by Mondrinos et al., in 2015, recognized that protein kinase C-ẟ (PKC-ẟ) acts as a critical regulator of the acute inflammatory response and demonstrated that PKCẟ inhibition was lung-protective in a rodent sepsis model. This theory has suggested that targeting PKCẟ is a potential strategy for preserving pulmonary function in indirect lung injuries. Intratracheally delivery of PKC-ẟ-TAT at the time of CLP surgery significantly reduced activation (tyrosine

Peptide and protein conjugated anticancer drugs administered to lung tissues

GNR-Dox-Tf-NPs (gold nanorod-doxorubicin-transferrin-nanoparticles) system carries doxorubicin conjugated to a pH-sensitive linker for anchoring to the transferrin receptor overexpressed in treatment of lung cancer. The targeting and pH-responsive drug release properties of GNR-Dox-Tf-NP enhanced the effectiveness of the therapeutic agent in cancer cells by inducing apoptosis and DNA damage [164]. cRGDyK peptide is a ligand that can target tumors via specific binding integrin receptor

Peptide and protein conjugated anti-tubercular drugs administered to lung tissues

A study conducted by Tsapis et al. (2003) revealed that formulating para-aminosalicylic acid (PAS) into large porous particles (LPPs) had an optimum deposition throughout the respiratory tract. Hence, insufflation of LPP-PAS provided a greater lung exposure, and this could potentially reduce the total dose required to achieve a higher local drug concentration and similar peak systemic drug concentration compared to oral PAS dosing [189]. On the other hand, Jawahar et al. (2012) documented

Virus/bacteria/fungi based protein and peptide biologics for pulmonary delivery

Adenovirus plays an important role as a vector in gene therapy. Sarkioja et al. (2006) discovered that the adenoviruses serotype 5(Ad5) modified with polylysine (PK7), integrin binding RGD motif and Ad3 knob domain enhanced p53 gene transfer to NSCLC cell line in vitro compared to original Ad5. For instance, Ad5lucRGD and Adpk7(GL) have an increased infectivity towards NSCLC cells, in terms of luciferase expression. In addition, conditionally replicating oncolytic adenoviruses (CRAds) with the

Miscellaneous

Horvath et al., have illustrated the relationship between two poly-specific lung epithelial organic cation/carnitine transporters, OCTN1 and OCTN2 with the uptake of inhaled 2-adrenergic agonist and anticholinergic bronchodilators in the airway in the year 2007. From his proposal, cationic fluorophore 4-[4-(dimethylamino)-styryl]-N-methylpyridinium (ASP) is the alternative of positive charged molecule of bronchodilators such as albuterol and formoterol. ASP uptake is noticeable at apical part

Future perspectives

Despite the development of advanced protein and peptide drug delivery to the lungs, still there is insufficient fundamental data that can significantly explain the mode of action behind this advanced drug delivery in improving the respiratory disease therapy. Hence, it necessitates additional studies focused on the development of this new drug delivery approach. Moreover, the physicochemical properties of the drug as well as its compatibility with protein nature carriers needs to be further

Conclusion

Proteins and peptides find extensively applications in treating various diseases due to their high potency and specificity. Recent developments in biotechnology have shown that novel therapeutically active proteins and peptides has the potential to be involved in the advanced drug delivery targeting the lungs. The common examples of proteins and peptides recruited in advanced drug delivery system including virus, bacteria, fungi, peptide or polypeptides, endotoxin or cytotoxin, antituberculosis

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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