Review articlePolyelectrolyte complexes as prospective carriers for the oral delivery of protein therapeutics
Graphical abstract
Introduction
Therapeutic biomolecules (i.e., proteins, peptides, enzymes, nucleic acids, hormones, etc.) have only recently become readily available, owing to the advances in biotechnology, which enabled their large-scale manufacturing [1], [2]. Their increasing availability has improved the treatment options in many areas of biomedicine and their use for the therapy of several diseases is now a well-established clinical practice. In addition, the exceptional therapeutic efficacy and high selectivity of macromolecules as compared to conventional drugs has radically advanced the pharmaceutical industry, especially since the commercial launch of the recombinant human insulin [3], [4], [5], [6].
However, despite their potential advantages, the lability and structural complexity of biomolecules both restrict their delivery via other than parenteral routes and lead inevitably to the quest for novel approaches in order to treat or prevent various diseases [3], [4]. For example, the development of oral formulations of therapeutic proteins faces several hurdles along the GIT, rendering such molecules less appealing as drug candidates. More specifically, despite the convenience and non-invasive nature of the oral route, orally administered macromolecular drugs undergo severe presystemic degradation, and several issues (e.g., poor solubility and stability in the gastric environment, low intestinal permeability, etc.) need to be simultaneously addressed in order to exert their therapeutic effects [1], [4], [7]. Consequently, the development of galenic formulations providing robust clinical results is severely impeded.
Since the properties of the nanoscale entities are completely different from those of the bulk materials, the evolution of nanomedicine has become a key component for the future research in medical intervention [8], [9]. Formulation into nanoscale drug delivery vehicles has long been proposed as a means to facilitate the delivery of macromolecules to specific tissues or cells since the nanoscale dimensions offer high surface-to-volume ratio and allow interactions with biological systems at their structural size level [10], [11]. Accordingly, the formation of colloidal PECs is an interesting approach in this direction [11].
Polyelectrolyte complexes are spontaneously formed upon mixing oppositely charged polyelectrolytes (PEs) under certain conditions and have the unique ability to combine physicochemical properties of at least two PEs, along with a facile preparation procedure and responsiveness to various stimuli. Additionally, PECs can be formed in water, eliminating this way the use of organic solvents and attracting the interest of the pharmaceutical industry for oral drug delivery purposes [12], [13]. Since several macromolecules of high pharmaceutical importance are PEs, their association with PECs has been thoroughly investigated as a means to overcome the current limitations in their oral delivery. The present review article aims to provide an insight into the principles and mechanisms governing the interactions between PEs and summarizes the recent advances in the development of PECs as prospective carriers for the oral delivery of macromolecules.
Section snippets
The oral administration route
Various routes (i.e., nasal, oral, pulmonary, etc.) have been investigated and assessed for their potency as ideal administration pathways for macromolecular drugs, and among them, the oral route is the most extensively studied, [14] mainly due to its accessibility and non-invasive nature (i.e., high patient compliance) [15] as well as the potential benefits regarding safety and economical aspects [16]. The oral drug pathway utilizes the GIT for medication delivery and represents a systemic
PECs-aided oral protein delivery
The complexation between therapeutic agents of high pharmaceutical importance (e.g. proteins, DNA, etc.) and water-soluble polyelectrolytes has been thoroughly investigated. The laws and PE characteristics governing the interactions between proteins and oppositely charged polyelectrolytes, that lead to the formation of polyelectrolyte-protein complexes with exceptional properties [57] are extensively discussed below.
Conclusions
Despite the substantial experimental efforts over the past years, the feasibility of efficacious oral protein delivery is still under dispute and the translation of promising results from animal studies into commercial products is limited. Several strategies have been pursued to facilitate the absorption of orally administered macromolecules, among which, their formulation into drug delivery vehicles shows great potential. In this context, polyelectrolyte complexes have emerged as versatile
References (139)
- et al.
Oral protein delivery: current status and future prospect
React. Funct. Polym.
(2011) - et al.
Recent advances in nanocarrier-based mucosal delivery of biomolecules
J. Control. Release
(2012) - et al.
Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers
Adv. Drug Deliv. Rev.
(2012) Colloidal polyelectrolyte complexes of chitosan and dextran sulfate towards versatile nanocarriers of bioactive molecules
Eur. J. Pharm. Biopharm.
(2011)- et al.
Mucus permeating carriers: formulation and characterization of highly densely charged nanoparticles
Eur. J. Pharm. Biopharm.
(2015) - et al.
Is the oral route possible for peptide and protein drug delivery?
Drug Discov. Today
(2006) Intestinal permeation enhancers
J. Pharm. Sci.
(2000)- et al.
Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach
J. Control. Release
(2006) - et al.
Theory of polyelectrolytes in solutions and at surfaces
Prog. Polym. Sci.
(2005) - et al.
Structural requirements for intestinal absorption of peptide drugs
J. Control. Release
(1996)
The challenge of proteolytic enzymes in intestinal peptide delivery
J. Control. Release
Property profiling of biosimilar mucus in a novel mucus-containing in vitro model for assessment of intestinal drug absorption
Eur. J. Pharm. Biopharm.
Some biological issues in oral, controlled drug delivery
Adv. Drug Deliv. Rev.
Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues
Adv. Drug Deliv. Rev.
Micro- and macrorheology of mucus
Adv. Drug Deliv. Rev.
Advances in oral transmucosal drug delivery
J. Control. Release
Mucoadhesive nanoparticles may disrupt the protective human mucus barrier by altering its microstructure
PLoS ONE
Diffusion of macromolecules and virus-like particles in human cervical mucus
Biophys. J.
Scalable method to produce biodegradable nanoparticles that rapidly penetrate human mucus
J. Control. Release
Biological hydrogels as selective diffusion barriers
Trends Cell Biol.
Mucin structure, aggregation, physiological functions and biomedical applications
Curr. Opin. Colloid Interface Sci.
Mucosal drug delivery: barriers, in vitro models and formulation strategies
J. Drug Del. Sci. Technol.
Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects
Nano Today
Nanoemulsions coated with alginate/chitosan as oral insulin delivery systems: preparation, characterization, and hypoglycemic effect in rats
Int. J. Nanomed.
The use of inhibitory agents to overcome the enzymatic barrier to perorally administered therapeutic peptides and proteins
J. Control. Release
A mucoadhesive nanoparticulate system for the simultaneous delivery of macromolecules and permeation enhancers to the intestinal mucosa
J. Control. Release
Polyelectrolytes and their biological interactions
Biophys J.
Kinetic analysis of nanoparticulate polyelectrolyte complex interactions with endothelial cells
Biomaterials
New insights into the structure of polyelectrolyte complexes
J. Colloid Interface Sci.
Degradability of poly(l-lysine) and poly(DL-aminoserinate) complexed with a polyanion under conditions modelling physico-chemical characteristics of body fluids
J. Colloid Interface Sci.
A new drug nanocarrier consisting of polyarginine and hyaluronic acid
Eur. J. Pharm. Biopharm.
Oral insulin delivery by self-assembled chitosan nanoparticles: in vitro and in vivo studies in diabetic animal model
Mater. Sci. Eng. C
Probing insulin’s secondary structure after entrapment into alginate/chitosan nanoparticles
Eur. J. Pharm. Biopharm.
Development and characterization of new insulin containing polysaccharide nanoparticles
Colloids Surf. B Biointerfaces
Enteric-coated capsules filled with freeze-dried chitosan/poly(γ-glutamic acid) nanoparticles for oral insulin delivery
Biomaterials
Oral Delivery of Macromolecular Drugs. Barriers, Strategies and Future Trends
Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies
Nat. Rev. Drug Discov.
Challenges in the delivery of peptide drugs: an industry perspective
Ther. Delivery
A possible approach for oral drug delivery of nanoparticles
Cosmos
Structure and mechanism formation of polyelectrolyte complex obtained from PSS/PAH system: effect of molar mixing ratio, base-acid conditions, and ionic strength
Colloid Polym. Sci.
Multifunctional nanoparticulate polyelectrolyte complexes
Pharm. Res.
Sizing, shaping and pharmaceutical applications of polyelectrolyte complex nanoparticles
Adv. Polym. Sci.
Formation and properties of positively charged colloids based on polyelectrolyte complexes of biopolymers
Langmuir
New polyelectrolyte complex particles as colloidal dispersions based on weak synthetic and/or natural polyelectrolytes
Express Polym. Lett.
Drug delivery systems: an updated review
Int. J. Pharm. Investig.
Recent trends in oral drug delivery: a review
Recent Pat. Drug Deliv. Formul.
Pharmacology
Emerging trends in oral delivery of peptide and protein drugs
Crit. Rev. Ther. Drug Carr. Syst.
Gastrointestinal physiology (Chapter 7)
Cited by (63)
Advances in surface-modified nanometal-organic frameworks for drug delivery
2023, International Journal of PharmaceuticsProgress and prospects of polysaccharide-based nanocarriers for oral delivery of proteins/peptides
2023, Carbohydrate PolymersStructural characterization, stability, and cytocompatibility study of chitosan BaTiO<inf>3</inf>@ZnO:Er heterostructures
2023, International Journal of Biological MacromoleculesDesign and in vitro/in vivo Evaluation of Polyelectrolyte Complex Nanoparticles Filled in Enteric-Coated Capsules for Oral Delivery of Insulin
2023, Journal of Pharmaceutical SciencesCitation Excerpt :Thus, proteins can be easily conjugated by titration with polyelectrolytes. Conjugation of proteins with PECs can be achieved by mixing the protein with the same charged polyelectrolyte before forming the complex and then mixing with the opposite charged polyelectrolyte or adsorption to the surface of the preformed PEC.5 The spontaneous formation of PECs in this way eliminates the stability and biocompatibility problems of peptides and proteins caused by toxic organic solvents, high temperature, strong agitation effect, and chemicals used in the conventional production methods of nanoparticulate systems.6