Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmaceutical Technology".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 16194

Special Issue Editors

School of Pharmacy, Fudan University, Shanghai 201203, China
Interests: oral delivery; transdermal delivery; nasal delivery; delivery of biomacromolecules; nano drug delivery system; absorption mechanisms
Special Issues, Collections and Topics in MDPI journals
School of Pharmacy, Fudan University, Shanghai 201203, China
Interests: oral delivery; intravenous delivery; nose to brain delivery; nanocarrier based drug delivery systems; biological fate; near-infrared bioimaging
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peptides and proteins have recently become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. For examples, insulin and GLP-1 analogues have already been first-line antihyperglycemic medicines; monoclonal antibody drugs have demonstrated their superiority in treatment of cancers and immune diseases. However, delivery of peptides and proteins are more challenging than conventional chemicals owing to their distinctive properties, such as large molecular structure, chemical and conformational instability, short half-life, etc. Besides, limited by their poor permeability across biological membranes, therapeutic proteins and peptides are usually administered by injection.

It is noteworthy that more and more peptides and proteins would be developed as therapeutics, with the advances of biotechnology. Hence, developing versatile and efficient drug delivery systems would be an urgency, which has attracted tremendous efforts of scientists all over the world to alter the administration routes, prolong half-life or improve stability of peptides and proteins in recent decades. A few efforts have paid off, as some technologies have been pushed toward clinical trials or even clinics, such as Eligen® for sameglutide and nasal delivery for glucagon. This special issue aims at collecting manuscripts in delivery systems of peptides and proteins and figure out challenges, status quo and future development. Topics include formulation strategies, injectable delivery, oral delivery, nasal delivery, transdermal delivery, ocular delivery, long-acting delivery, targeted delivery of peptides and so on.

Prof. Dr. Jianping Qi
Prof. Dr. Haisheng He 
Guest Editors

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Keywords

  • proteins
  • peptides
  • delivery
  • oral
  • nasal
  • transdermal
  • ocular
  • long-acting
  • formulation

Published Papers (7 papers)

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Editorial

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2 pages, 179 KiB  
Editorial
Special Issue “Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives”
Pharmaceuticals 2023, 16(9), 1285; https://doi.org/10.3390/ph16091285 - 12 Sep 2023
Viewed by 652
Abstract
Peptides and proteins have emerged as more important therapeutic molecules compared to small molecular chemicals due to their high specificity and efficacy and low toxicity [...] Full article

Research

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19 pages, 2669 KiB  
Article
One-Step Pharmaceutical Preparation of PEG-Modified Exosomes Encapsulating Anti-Cancer Drugs by a High-Pressure Homogenization Technique
Pharmaceuticals 2023, 16(1), 108; https://doi.org/10.3390/ph16010108 - 11 Jan 2023
Cited by 4 | Viewed by 2479
Abstract
The use of exosomes encapsulating therapeutic agents for the treatment of diseases is of increasing interest. However, some concerns such as limited efficiency and scalability of conventional drug encapsulation methods to exosomes have still remained; thus, a new approach that enables encapsulation of [...] Read more.
The use of exosomes encapsulating therapeutic agents for the treatment of diseases is of increasing interest. However, some concerns such as limited efficiency and scalability of conventional drug encapsulation methods to exosomes have still remained; thus, a new approach that enables encapsulation of therapeutic agents with superior efficiency and scalability is required. Herein, we used RAW264 macrophage cell-derived exosomes (RAW-Exos) and demonstrated that high-pressure homogenization (HPH) using a microfluidizer decreased their particle size without changing their morphology, the amount of exosomal marker proteins, and cellular uptake efficiency into RAW264 and colon-26 cancer cells. Moreover, HPH allowed for modification of polyethylene glycol (PEG)-conjugated lipids onto RAW-Exos, as well as encapsulation of the anti-cancer agent doxorubicin. Importantly, the doxorubicin encapsulation efficiency became higher upon increasing the process pressure and simultaneous HPH with PEG-lipids. Moreover, treatment with PEG-modified RAW-Exos encapsulating doxorubicin significantly suppressed tumor growth in colon-26-bearing mice. Taken together, these results suggest that HPH using a microfluidizer could be useful to prepare PEG-modified Exos encapsulating anti-cancer drugs via a one-step pharmaceutical process, and that the prepared functional Exos could be applied for the treatment of cancer in vivo. Full article
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11 pages, 1763 KiB  
Article
Kreon® (Creon®) vs. Lipancrea®: In Vitro Comparison of Two Encapsulated Pancreatin Preparations
Pharmaceuticals 2022, 15(12), 1570; https://doi.org/10.3390/ph15121570 - 16 Dec 2022
Cited by 3 | Viewed by 1578
Abstract
Kreon® (Creon®) and Lipancrea® are pancreatic enzyme supplements indicated in the treatment of exocrine pancreatic insufficiency. In order to determine their interchangeability, an in vitro comparison of their physical properties and enzymatic activity was carried out. Capsule fill weight [...] Read more.
Kreon® (Creon®) and Lipancrea® are pancreatic enzyme supplements indicated in the treatment of exocrine pancreatic insufficiency. In order to determine their interchangeability, an in vitro comparison of their physical properties and enzymatic activity was carried out. Capsule fill weight and particle size were also determined in order to establish their physical properties. Amylase, lipase and protease activities, lipase release at different pHs and the dissolution time of pellets were assessed for enzymatic analysis. The length range of Kreon® and Lipancrea® pellets was 1.1–2.2 mm and 1.5–2.8 mm, respectively. Protease activity was below the label claim for Lipancrea® and above for Kreon® presentations. Lipase and amylase activity were equal to or higher than the label claim in both preparations. In dissolution experiments simulating the stomach passage, significant release of lipase activity was observed for Lipancrea® (% actual activity: 41% for Lipancrea® 8000; 21% for Lipancrea® 16000) after 60 min at pH 5.0. No release of lipase activity was observed for Kreon® at that particular pH. Enzyme release for Lipancrea® at pH 6.0 was generally slower than for Kreon® and seemed to be influenced by the preceding incubation at lower pH. More than 85% of Kreon® and Lipancrea® dissolved in a pH 6.0 phosphate buffer within 20 min. Despite the similarities of the enzyme content on the respective labels, Kreon® and Lipancrea® differ in pellet size, enzymatic activity and release. This may impact their therapeutic efficacy and, therefore, may limit their interchangeability. Full article
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Review

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17 pages, 2002 KiB  
Review
Local Delivery Strategies for Peptides and Proteins into the CNS: Status Quo, Challenges, and Future Perspectives
Pharmaceuticals 2023, 16(6), 810; https://doi.org/10.3390/ph16060810 - 30 May 2023
Cited by 3 | Viewed by 1716
Abstract
Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry [...] Read more.
Over the past decades, peptides and proteins have been increasingly important in the treatment of various human diseases and conditions owing to their specificity, potency, and minimized off-target toxicity. However, the existence of the practically impermeable blood brain barrier (BBB) limits the entry of macromolecular therapeutics into the central nervous systems (CNS). Consequently, clinical translation of peptide/protein therapeutics for the treatment of CNS diseases has been limited. Over the past decades, developing effective delivery strategies for peptides and proteins has gained extensive attention, in particular with localized delivery strategies, due to the fact that they are capable of circumventing the physiological barrier to directly introduce macromolecular therapeutics into the CNS to improve therapeutic effects and reduce systemic side effects. Here, we discuss various local administration and formulation strategies that have shown successes in the treatment of CNS diseases using peptide/protein therapeutics. Lastly, we discuss challenges and future perspectives of these approaches. Full article
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14 pages, 1482 KiB  
Review
Recent Advances in Oral Peptide or Protein-Based Drug Liposomes
Pharmaceuticals 2022, 15(9), 1072; https://doi.org/10.3390/ph15091072 - 28 Aug 2022
Cited by 6 | Viewed by 2468
Abstract
The high physiology and low toxicity of therapeutic peptides and proteins have made them a hot spot for drug development in recent years. However, their poor oral bioavailability and unstable metabolism make their clinical application difficult. The bilayer membrane of liposomes provides protection [...] Read more.
The high physiology and low toxicity of therapeutic peptides and proteins have made them a hot spot for drug development in recent years. However, their poor oral bioavailability and unstable metabolism make their clinical application difficult. The bilayer membrane of liposomes provides protection for the drug within the compartment, and their high biocompatibility makes the drug more easily absorbed by the body. However, phospholipids—which form the membranes—are subjected to various digestive enzymes and mucosal adhesion in the digestive tract and disintegrate before absorption. Improvements in the composition of liposomes or modifying their surface can enhance the stability of the liposomes in the gastrointestinal tract. This article reviews the basic strategies for liposome preparation and surface modification that promote the oral administration of therapeutic polypeptides. Full article
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22 pages, 2116 KiB  
Review
Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules
Pharmaceuticals 2022, 15(7), 877; https://doi.org/10.3390/ph15070877 - 16 Jul 2022
Cited by 9 | Viewed by 4612
Abstract
Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular [...] Read more.
Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations. Full article
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Other

10 pages, 516 KiB  
Perspective
Low Drug Loading Hampers the Clinical Translation of Peptide Drugs-Containing Metered-Dose Inhalers
Pharmaceuticals 2022, 15(4), 389; https://doi.org/10.3390/ph15040389 - 23 Mar 2022
Cited by 2 | Viewed by 1669
Abstract
Peptide-based drugs have attracted extensive attention from the medical and pharmaceutical industry because of their relatively high safety and efficacy. However, most of the peptide drugs approved are administrated by injection, which can easily cause poor patient compliance. In this circumstance, pulmonary administration [...] Read more.
Peptide-based drugs have attracted extensive attention from the medical and pharmaceutical industry because of their relatively high safety and efficacy. However, most of the peptide drugs approved are administrated by injection, which can easily cause poor patient compliance. In this circumstance, pulmonary administration as an alternative to injection administration can not only avoid the above issue but also accelerate the absorption rate of peptide drugs and improve bioavailability. Among the pulmonary delivery systems available on the market, metered-dose inhalers (MDIs) have emerged as appealing candidates for pulmonary delivery systems with clinical translational value, owing to their many merits, including portable, easy-to-operate, and cost-effective properties. Nevertheless, the industrialization of peptide drugs-containing MDIs encounters a bottleneck of low drug loading, owing to the incompatibility between the propellant and the peptide drugs, which cannot be effectively overcome by the current carrier particle encapsulation strategy. Herein, we put forward the following strategies: (1) To screen amphiphilic materials with high surface activity and strong interaction with peptide drugs; (2) To construct a chemical connection between peptide drugs and amphiphilic substances; (3) To optimize the cosolvent for dispersing peptide drugs. We suppose these strategies have the potential to defeat the bottleneck problem and provide a new idea for the industrialization of peptide drugs-containing MDIs. Full article
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