Clinical perspectives on pulmonary systemic and macromolecular delivery

Scheuch, G.; Kohlhaeufl, Martin; Brand, Peter; Siekmeier, R.

doi:10.1016/j.addr.2006.07.009

Cited by 152 publications

(100 citation statements)

References 26 publications

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“…Despite its perceived potential, progress to market in the area of systemic delivery of proteins has been slow to-date due to a number of confounding factors including rapid clearance, instability [33], risks of immunogenicity [33] and longterm toxicity, dosing issues [28] and limited additives licensed for inhalation. These issues have been covered in some detail in recent reviews [29,30].…”

Section: Drug Candidates For Systemic Delivery Via the Lungsmentioning

confidence: 99%

“…Two proteins for inhalation are currently available on the market DNase (locally acting mucolytic for Cystic fibrosis) and now to the delight and relief of many working in the field, insulin. A wide range of other proteins and peptides for systemic delivery via the lungs are being investigated, including calcitonin, growth hormone, immunoglobulins, and granulocyte colony-stimulating factor (G-CSF) to name a few (Table 1) The advantages of this route for macromolecular delivery are well documented and recently reviewed [7,28,5,29,30], with the molecular weight of a given macromolecular drug candidate impacting significantly on the rate of absorption [31,32] and metabolism [7,5]. Despite its perceived potential, progress to market in the area of systemic delivery of proteins has been slow to-date due to a number of confounding factors including rapid clearance, instability [33], risks of immunogenicity [33] and longterm toxicity, dosing issues [28] and limited additives licensed for inhalation.…”

Section: Drug Candidates For Systemic Delivery Via the Lungsmentioning

confidence: 99%

See 1 more Smart Citation

In vivo animal models for drug delivery across the lung mucosal barrier☆

Cryan

Sivadas

García-Contreras

2007

Advanced Drug Delivery Reviews

128

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Section: Drug Candidates For Systemic Delivery Via the Lungsmentioning

confidence: 99%

Section: Drug Candidates For Systemic Delivery Via the Lungsmentioning

confidence: 99%

In vivo animal models for drug delivery across the lung mucosal barrier☆

Cryan

Sivadas

García-Contreras

2007

Advanced Drug Delivery Reviews

128

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“…3,4) Recently, the lung has attracted a great deal of interest as an alternative administration route for protein and peptide drugs. 3,5) The inhalation pulmonary delivery system, which may enable the systemic absorption of protein and peptide drugs, has been extensively studied.6) In particular, clinical research on inhaled insulin has confirmed the efficacy and safety of inhaled insulin in the treatment of diabetes mellitus. 7) In addition, the bioavailability of inhaled insulin via the lung is greater compared to other non-invasive routes such as the gut and nose.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Mechanism of Insulin Uptake in Rat Alveolar Type II and Type I-Like Epithelial Cells

Ikehata

Yumoto

Kato

et al. 2009

Biological & Pharmaceutical Bulletin

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The alveolar epithelium is comprised of type II and type I cells, which are two morphologically and functionally different epithelial cells. Alveolar type I cells, which are squamous and cover more than 90% of the alveolar surface area, play a major role in gas exchange. 1,2) On the other hand, alveolar type II cells are cuboidal and outnumber type I cells, although type II cells occupy less than 10% of the surface area even when their apical microvilli are taken into consideration.1,2) In addition, type II cells have multiple functions such as surfactant production and secretion, and serve as type I cell progenitors.2)The majority of protein and peptide therapeutic drugs were developed as injection formulations, and have a variety of problems, especially for patients, in terms of safety, pain, and needle phobia. 3,4) Recently, the lung has attracted a great deal of interest as an alternative administration route for protein and peptide drugs. 3,5) The inhalation pulmonary delivery system, which may enable the systemic absorption of protein and peptide drugs, has been extensively studied.6) In particular, clinical research on inhaled insulin has confirmed the efficacy and safety of inhaled insulin in the treatment of diabetes mellitus. 7) In addition, the bioavailability of inhaled insulin via the lung is greater compared to other non-invasive routes such as the gut and nose. 8)Previous studies concerning protein transport across alveolar epithelia have suggested that the transport system most likely to be involved is endocytosis. 9) We also have studied the transport of albumin in alveolar epithelial cells, and found that albumin is internalized into type II and type I cells via a clathrin-mediated endocytic pathway with greater uptake activity in type II cells than in type I cells.10) These findings indicate that despite the much smaller surface area of type II cells compared to type I cells, type II cells most likely play an important role in the endocytic transport of proteins in alveolar epithelia.In the case of small proteins (peptides) such as insulin, both paracellular and transcellular routes may be involved in alveolar epithelial transport.1) Bur et al. 11) reported that in human primary cultured alveolar type I-like epithelial cells, the apparent permeability coefficient of insulin was comparable to that reported for dextran, indicating that a specific, transcellular transport process is not involved. On the other hand, the alveolar epithelial junction was reported to be tighter than other epithelia, 1) suggesting that the contribution of a paracellular route for insulin in alveolar epithelial transport may not be so high. Furthermore, it has been reported that megalin serves as an endocytic receptor for insulin uptake in rat renal proximal tubule cells, 12) and that megalin is also expressed in alveolar epithelial cells.13) Thus, it is possible that an endocytic pathway is involved in insulin transport in alveolar epithelia. However, little information is available concerning the handling of insu...

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“…The application of inhalation in the delivery of conventional drugs as well as novel therapeutics (e.g., proteins, genes, siRNA, etc.) has been well addressed in several recent reviews (1)(2)(3). On the other hand, drug delivery to pulmonary endothelial cells (ECs) via airway is rather inefficient, and new strategies are being developed for systemic delivery of various types of therapeutic agents to pulmonary circulation including conventional drugs (4), radioisotopes (5), protein therapeutics (6), etc.…”

Section: Introductionmentioning

confidence: 99%

Targeted Delivery of Nucleic Acid-Based Therapeutics to the Pulmonary Circulation

Kuruba

Wilson

Gao

et al. 2009

AAPS J

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Abstract. Targeted delivery of functional nucleic acids (genes and oligonucleotides) to pulmonary endothelium may become a novel therapy for the treatment of various types of lung diseases. It may also provide a new research tool to study the functions and regulation of novel genes in pulmonary endothelium. Its success is largely dependent on the development of a vehicle that is capable of efficient pulmonary delivery with minimal toxicity. This review summarizes the recent progress that has been made in our laboratory along these research directions. Factors that affect pulmonary nucleic acids delivery are also discussed.

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Clinical perspectives on pulmonary systemic and macromolecular delivery

Cited by 152 publications

References 26 publications

In vivo animal models for drug delivery across the lung mucosal barrier☆

In vivo animal models for drug delivery across the lung mucosal barrier☆

Mechanism of Insulin Uptake in Rat Alveolar Type II and Type I-Like Epithelial Cells

Targeted Delivery of Nucleic Acid-Based Therapeutics to the Pulmonary Circulation

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