Translation of pulmonary protein therapy from bench to bedside: Addressing the bioavailability challenges

Sodha, Srushti; Patel, M.; Nagarkar, Rigved; Mohammed, Irfan Ali; Patel, Hiren

doi:10.1016/j.jddst.2021.102664

Cited by 7 publications

(5 citation statements)

References 135 publications

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“…The transportation of proteins from the pulmonary region to the bloodstream or lymphatic circulation necessitates overcoming the alveolar epithelium, which is fortified by tight interconnections among epithelial cells. [ 36 ] These tight junctions, as narrow as 0.5–0.9 nanometers, serve as a crucial obstruction, impeding the absorption of protein drugs into the systemic or lymphatic circulation. [ 37 ] Biomacromolecules mainly traverse lung epithelium through transcytosis or paracellular transport.…”

Section: Barriers To Pulmonary Delivery Of Proteinsmentioning

confidence: 99%

Advances in Pulmonary Protein Delivery Systems

Zhao,

Liu,

2024

Advanced NanoBiomed Research

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Protein‐based therapeutics and vaccines play a pivotal role in the realm of biomedical science. Pulmonary administration offers several advantages including rapid adsorption, non‐invasive, increased local drug concentration, and bypassed first‐pass metabolism, thus holding great potential to address multiple unmet medical needs in lung‐related diseases and vaccination. However, the limited success of inhaled proteins in clinical settings highlights the challenges associated with protein stability and the physiological barriers within the respiratory system. To overcome these hurdles, a variety of delivery systems including polymers, liposomes, cell‐derived membranes, and inorganic materials are developed to improve the stability, mucus penetration, retention time, and bioavailability of proteins. With the outbreak of COVID‐19, the pulmonary administration of proteins has drawn great attention. In this review, the design principle, preparation, biomedical application, progress in clinical translation, advantages, and disadvantages of each kind of delivery system are summarized, with an emphasis on carrier materials.

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Section: Barriers To Pulmonary Delivery Of Proteinsmentioning

confidence: 99%

Advances in Pulmonary Protein Delivery Systems

Zhao,

Liu,

2024

Advanced NanoBiomed Research

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“…This low permeability stems from the relative lack of diffusion of large biomolecules across intact epithelial tissue, in addition to ubiquitous chemical and enzymatic proteolysis. In this regard, pulmonary dosage forms may behave more favorably due to a large surface area, a high degree of vascularization, and relatively thin mucosal barriers [ 60 ]. In any case, mucosal adjuvant formulation development efforts may be needed to target cell uptake by resident antigen-presenting cells, which can sample antigens from across the epithelial barrier and then present them to effector subsets in the draining lymph node.…”

Section: Alternative Routes Of Deliverymentioning

confidence: 99%

Practical Considerations for Next-Generation Adjuvant Development and Translation

Lykins

Fox

2023

Pharmaceutics

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Over the last several years, there has been increased interest from academia and the pharmaceutical/biotech industry in the development of vaccine adjuvants for new and emerging vaccine modalities. Despite this, vaccine adjuvant development still has some of the longest timelines in the pharmaceutical space, from discovery to clinical approval. The reasons for this are manyfold and range from complexities in translation from animal to human models, concerns about safety or reactogenicity, to challenges in sourcing the necessary raw materials at scale. In this review, we will describe the current state of the art for many adjuvant technologies and how they should be approached or applied in the development of new vaccine products. We postulate that there are many factors to be considered and tools to be applied earlier on in the vaccine development pipeline to improve the likelihood of clinical success. These recommendations may require a modified approach to some of the common practices in new product development but would result in more accessible and practical adjuvant-containing products.

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“…Degradation of inhaled proteins and peptides could occur upon deposited in the respiratory tract or transported through the lung epithelium. The degree of enzymatic hydrolysis is drug molecular weight-dependent, presenting a higher metabolization for small natural peptides with less than 30 amino acids, compared with the proteins containing greater tertiary and quaternary structure [18]. In general, proteins with molecular weight ranging from 6 and 50 kDa are relatively resistant to ubiquitous peptidases with good bioavailability following inhalation, partially because the ends of their amino acid chains are frequently tucked inside the globular structure of proteins and are not accessible for hydrolysis.…”

Section: Protease and Peptidase Metabolizationmentioning

confidence: 99%

“…Huang and Zhao et al revealed that insulin-loaded nanoparticles made from low-molecular-weight chitosan and poloxamer 188 modified gelatin promoted insulin pulmonary absorption effectively, and showed good relative pharmacological bioavailability of 73.7% and 76.4% in comparison with subcutaneously administered insulin solution, respectively [115,116]. Notable, too, is the toxicity issues of polymer accumulation within the lungs [18]. Nanoparticles, unlike micron fragments, are less accessible to alveolar macrophages and are usually retained in the alveoli for a long time upon inhalation, which could result in the potential hazard to lung epithelium.…”

Section: Polymeric Nanoparticlesmentioning

confidence: 99%

“…Once aerosolized, the PNAPs deposit homogeneously on alveolar epithelial cells surface owing to their optimal aerodynamic particle size, and subsequently, the nanoparticles are released into the lung lining fluids and are retained for a longer period due to their resistance to immune cells. The Trojan particles combine the advantages of polymeric nanoparticles and porous microparticles such as high drug loading, superior mucus penetration and lung retention capacity, as well as favorable aerodynamic characteristics [18]. Alfagih et al developed bovine serum albumin (BSA)loaded nanoparticles using a biodegradable polymer poly [12].…”

Section: Chitosan/ Mannitolmentioning

confidence: 99%

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Challenges and Strategies to Enhance the Systemic Absorption of Inhaled Peptides and Proteins

Lü

Cui

et al. 2022

Pharm Res

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Proteins and peptides-based therapeutics are making substantial access to the market due to their obvious advantages of strong potency, high specificity and desirable safety profile. However, most clinical products are mainly delivered via parenteral route with inferior convenience. Lung is an attractive non-invasive alternative passage for systemic administration of biologics with numerous outstanding features, as examples of large absorptive surface area, extensive vascularization and mild local microenvironment. Even so, mucociliary clearance, alveolar macrophage phagocytosis, enzymatic metabolism, pulmonary surfactant adsorption and limited epithelium permeability constitute major obstacles affecting the systemic absorption of inhaled proteins and peptides. This article begins by giving a brief overview of challenges for the systemic absorption of inhaled proteins and peptides, and then goes on to a comprehensive review of possible strategies for enhanced pulmonary absorption, including chemical modification, addition of protease inhibitors, incorporation of absorption enhancers, modification with fusion proteins and development of particulate-based drug delivery systems. These strategies can provide enhanced transmembrane absorption capacity while avoiding pulmonary clearance, offering a valuable reference for designing pulmonary delivery systems of protein and peptide drugs.

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Translation of pulmonary protein therapy from bench to bedside: Addressing the bioavailability challenges

Cited by 7 publications

References 135 publications

Advances in Pulmonary Protein Delivery Systems

Advances in Pulmonary Protein Delivery Systems

Practical Considerations for Next-Generation Adjuvant Development and Translation

Challenges and Strategies to Enhance the Systemic Absorption of Inhaled Peptides and Proteins

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