Application of permeation enhancers in oral delivery of macromolecules: an update

The application of permeation enhancers (PEs) to improve transport of poorly absorbed active pharmaceutical ingredients across the intestinal epithelium is a widely tested approach. Several hundred compounds have been shown to alter the epithelial barrier, and although the research emphasis has broadened to encompass a role for nanoparticle approaches, PEs represent a key constituent of conventional oral formulations that have progressed to clinical testing. In this review, we highlight promising PEs in early development, summarize the current state of the art, and highlight challenges to the translation of PE-based delivery systems into safe and effective oral dosage forms for patients

Biomedical applications of amino acid-modified chitosans: a review

The presence of reactive primary amines in the backbone structure of chitosan, enables the derivatisation with different functional groups and thereby improving and expanding its properties, such as solubility and mucoadhesiveness, for biomedical applications. Such derivatives can be exploited with good results in a number of biomedical areas, including enhancement of nucleic acid transfection in gene therapy, as well as many other applications aiming to maximize drug delivery and aiding tissue engineering. The aim of this review is to provide an up to date overview of the methods used for derivatizing the chitosan with amino acids and to discuss the characteristics and potential biomedical application of the different amino acid derivatized chitosans described in the literature.</p

PEGylated chitosan derivatives: synthesis, characterizations and pharmaceutical applications

This review sets out to describe and discuss the synthetic approaches and the fields of application of PEGylated chitosan copolymers especially for medical use. The PEGylation of chitosan and chitosan derivatives is able to add new physicochemical properties to the cationic polysaccharide polymers, thereby overcoming some limitations, especially regarding their solubility and their use in drug and gene delivery (DNA and siRNA). All methods of derivatization have been considered and described together with the different methods of characterization of the copolymers. The capacities of PEGylated chitosan to reduce chitosan toxicity, to enhance membrane permeation and to form thermosensitive hydrogels have also been discussed.</p

Effect of PEGylation on the toxicity and permeability enhancement of chitosan

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (M w 1.9 and 5.0 × 10 3 g mol -1) to chitosans (M w 28.9 and 82.0 × 10 3 g mol -1) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, 1H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose.</p

Biomedical applications of amino acid-modified chitosans: a review

The presence of reactive primary amines in the backbone structure of chitosan, enables the derivatisation with different functional groups and thereby improving and expanding its properties, such as solubility and mucoadhesiveness, for biomedical applications. Such derivatives can be exploited with good results in a number of biomedical areas, including enhancement of nucleic acid transfection in gene therapy, as well as many other applications aiming to maximize drug delivery and aiding tissue engineering. The aim of this review is to provide an up to date overview of the methods used for derivatizing the chitosan with amino acids and to discuss the characteristics and potential biomedical application of the different amino acid derivatized chitosans described in the literature.</p

PEGylated chitosan derivatives: synthesis, characterizations and pharmaceutical applications

This review sets out to describe and discuss the synthetic approaches and the fields of application of PEGylated chitosan copolymers especially for medical use. The PEGylation of chitosan and chitosan derivatives is able to add new physicochemical properties to the cationic polysaccharide polymers, thereby overcoming some limitations, especially regarding their solubility and their use in drug and gene delivery (DNA and siRNA). All methods of derivatization have been considered and described together with the different methods of characterization of the copolymers. The capacities of PEGylated chitosan to reduce chitosan toxicity, to enhance membrane permeation and to form thermosensitive hydrogels have also been discussed.</p

Effect of PEGylation on the toxicity and permeability enhancement of chitosan

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (M w 1.9 and 5.0 × 10 3 g mol -1) to chitosans (M w 28.9 and 82.0 × 10 3 g mol -1) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, 1H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose.</p

Effect of PEGylation on the Toxicity and Permeability Enhancement of Chitosan

The aim of the present work is to investigate if conditions can be devised where PEGylation of chitosan would reduce its toxicity toward the nasal mucosa while maintaining its ability to open the cellular tight junctions and, consequently, produce an enhancement of macromolecular permeability. A series of mPEG-g-chitosan copolymers with varying levels of mPEG substitution, mPEG molecular weight, and chitosan molecular weight were synthesized by grafting carboxylic acid-terminated mPEGs (Mw 1.9 and 5.0 × 103 g mol−1) to chitosans (Mw 28.9 and 82.0 × 103 g mol−1) using a NHS/EDC coupling system. The synthesized mPEG-g-chitosans were fully characterized using a number of techniques, including FT-IR, 1H NMR, and SEC-MALLS and their physicochemical properties were analyzed by TGA and DSC. Thereafter, the conjugates were tested for their cytotoxicity and tight junction modulating property in a relevant cell model, a mucus producing Calu-3 monolayer. mPEG-g-chitosan conjugates exhibited reduced toxicity toward cells, as compared to unmodified chitosan counterparts. Furthermore, the conjugates demonstrated a dramatic effect on cell monolayer transepithelial electrical resistance (TEER) and enhancement of permeability of model macromolecules. TEER and permeability-enhancing effects, as measurable indicators of tight junction modulation, were found to be pH-dependent and were notably more pronounced than those exhibited by unmodified chitosans. This work therefore demonstrates that conditions can be contrived where PEGylation improves the toxicity profile of chitosan, while preserving its effect on epithelial tight junctions in the nose

Folic acid conjugated chitosan nanoparticles for tumor targeting of therapeutic and imaging agents

Anticancer drugs are typically distributed non-specifically in the body, where they affect both cancerous and normal cells. This limits the drug level achievable within the tumor, compromising the therapeutic efficacy, and results in potential toxic effects on normal tissues. Targeted delivery of chemotherapeutics exclusively to cancer cells is the focus of intensive research for improvement of anticancer therapy. Various drug delivery systems have been investigated for this purpose, with therapeutic-carrying polymeric nanoparticulate systems designed for specific targeting of tumor cells receiving special interest. Chitosan, a natural polymer derived from crustacean shells, has attracted particular attention as a drug carrier. The simple and mild preparation methods, low toxicity, good stability, controlled drug release and the ability to overcome biological barriers has made chitosan-based nanoparticles popular in drug and gene delivery applications. Chitosan nanoparticles have been fabricated with optimal size and surface characteristics in order to tailor the behavior within the biological system, including circulation time, as well as passive and active cancer targeting. Folic acid is widely employed as a ligand targeting cancerous cells as its receptor which 'shuttles' folic acid into the cells via endocytosis is over-expressed on the surface of many human epithelial cancer cells. Incorporating folic acid into chitosan-based drug and gene delivery formulations renders the systems with an efficient targeting capacity. Furthermore, it is possible to formulate chitosan nanocarriers that display multiple useful characteristics extending beyond targeted delivery. The versatility of these systems is also being exploited in nanotheranostics.</p

Folic acid conjugated chitosan nanoparticles for tumor targeting of therapeutic and imaging agents

Anticancer drugs are typically distributed non-specifically in the body, where they affect both cancerous and normal cells. This limits the drug level achievable within the tumor, compromising the therapeutic efficacy, and results in potential toxic effects on normal tissues. Targeted delivery of chemotherapeutics exclusively to cancer cells is the focus of intensive research for improvement of anticancer therapy. Various drug delivery systems have been investigated for this purpose, with therapeutic-carrying polymeric nanoparticulate systems designed for specific targeting of tumor cells receiving special interest. Chitosan, a natural polymer derived from crustacean shells, has attracted particular attention as a drug carrier. The simple and mild preparation methods, low toxicity, good stability, controlled drug release and the ability to overcome biological barriers has made chitosan-based nanoparticles popular in drug and gene delivery applications. Chitosan nanoparticles have been fabricated with optimal size and surface characteristics in order to tailor the behavior within the biological system, including circulation time, as well as passive and active cancer targeting. Folic acid is widely employed as a ligand targeting cancerous cells as its receptor which 'shuttles' folic acid into the cells via endocytosis is over-expressed on the surface of many human epithelial cancer cells. Incorporating folic acid into chitosan-based drug and gene delivery formulations renders the systems with an efficient targeting capacity. Furthermore, it is possible to formulate chitosan nanocarriers that display multiple useful characteristics extending beyond targeted delivery. The versatility of these systems is also being exploited in nanotheranostics.</p