Liposomes — microscopic phospholipid bubbles with a bilayered membrane structure — have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs — from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Recent advances with liposomes as pharmaceutical carriers.

Liposomal drug delivery systems: from concept to clinical applications.

Poly(ethylene glycol) (PEG) is the most used polymer and also the gold standard for stealth polymers in the emerging field of polymer-based drug delivery. The properties that account for the overwhelming use of PEG in biomedical applications are outlined in this Review. The first approved PEGylated products have already been on the market for 20 years. A vast amount of clinical experience has since been gained with this polymer--not only benefits, but possible side effects and complications have also been found. The areas that might need consideration and more intensive and careful examination can be divided into the following categories: hypersensitivity, unexpected changes in pharmacokinetic behavior, toxic side products, and an antagonism arising from the easy degradation of the polymer under mechanical stress as a result of its ether structure and its non-biodegradability, as well as the resulting possible accumulation in the body. These possible side effects will be discussed in this Review and alternative polymers will be evaluated.

Poly(ethylene glycol) in Drug Delivery: Pros and Cons as Well as Potential Alternatives

PLGA-based nanoparticles: An overview of biomedical applications

Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.

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Transdermal drug delivery

The lipid matrix present in the human stratum corneum (the thin, uppermost layer of the skin) is considered to play a crucial role in the skin barrier function. The lipid matrix consists of ceramides, cholesterol, and free fatty acids. The 13 nm lamellar phase present in the lipid matrix of the stratum corneum is very characteristic and plays an important role in the skin barrier function. One subclass of ceramides with a linoleic acid linked to a very long acyl (referred to as EOS) plays a crucial role in the formation of the 13 nm lamellar phase. In this article, we focus on the lipid phase behavior of EOS mixed with cholesterol or with cholesterol and free fatty acids. Our studies reveal that an equimolar ratio of EOS, cholesterol, and free fatty acids forms a lamellar phase with a very long repeat distance of approximately 14.7 nm. This phase exhibits exceptional behavior in that in the thermotropic response the fatty acid chains and the ceramide chains undergo an order−disorder transition in differen...

Model Membranes Prepared with Ceramide EOS, Cholesterol and Free Fatty Acids Form a Unique Lamellar Phase

Therapeutic vaccination with synthetic long peptides (SLP) can be clinically effective against HPV-induced premalignant lesions; however, their efficiency in established malignant lesions leaves room for improvement. Here, we report the high therapeutic potency of cationic liposomes loaded with well-defined tumor-specific SLPs and a TLR3 ligand as adjuvant. The cationic particles, with an average size of 160 nm, could strongly activate functional, antigen-specific CD8+ and CD4+ T cells and induced in vivo cytotoxicity against target cells after intradermal vaccination. At a low dose (1 nmol) of SLP, our liposomal formulations significantly controlled tumor outgrowth in two independent models (melanoma and HPV-induced tumors) and even cured 75%-100% of mice of their large established tumors. Cured mice were fully protected from a second challenge with an otherwise lethal dose of tumor cells, indicating the potential of liposomal SLP in the formulation of powerful vaccines for cancer immunotherapy. Cancer Immunol Res; 5(3); 222-33. ©2017 AACR.

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Efficient Eradication of Established Tumors in Mice with Cationic Liposome-Based Synthetic Long-Peptide Vaccines

Thermal analysis of water in p(HEMA) hydrogels

Microneedles are needle-like structures shorter than 1 mm that have been advocated as devices for enabling potentially pain-free intradermal delivery of biomacromolecules (1–5). To permit a reproducible delivery of the drug, microneedles should be inserted into the skin in a controlled and reproducible manner (4,6). Obviously, one of the factors that influence the penetration ability of microneedles is the insertion process itself, e.g., microneedles can be inserted manually or by using insertion devices (3,4,6–9). Recently, the penetration ability of low-density arrays (42 microneedles/cm2) with 750-μm long microneedles, applied manually or by using a snap-based applicator, was investigated (10). However, no studies have been reported on the efficiency and reproducibility of the insertion of high-density microneedles into human skin. Therefore, the aim of this study was to investigate the effect of the type of application on inter and intra individual variability of microneedle insertion into human skin by microneedle users.

We show that participants using an impact-insertion applicator inserted high-density microneedles into ex vivo human skin with high efficiency and with a low inter and intra individual variation. However, when the same microneedle arrays were inserted by using a manual insertion device, the penetration efficiency was reduced by approximately 40% with a considerably lower reproducibility. Finally, the applicability of an impact-insertion applicator/microneedle array was confirmed in a vaccination study in mice.

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Impact-insertion applicator improves reliability of skin penetration by solid microneedle arrays.

The outer part of the skin, stratum corneum, is essential to the skin's barrier function. Monolayer and bulk phase behavior of stratum corneum model lipids have thus been studied. Domain formation in Langmuir−Blodgett monolayers of synthetic ceramides (C16CerIII and C24CerIII), cholesterol, and free fatty acids (lignoceric acid, C24:0, and palmitic acid, C16:0) were investigated by atomic force microscopy. Binary, ternary, and more complex lipid mixtures were examined. It was shown that small amounts of ceramide are miscible in a cholesterol-rich phase with the miscibility dependent upon the ceramide chain length. Two phases are formed at low and intermediate cholesterol concentrations. In the ceramide−cholesterol monolayers, very small rectangular-shaped ceramide domains thought to be two-dimensional single ceramide crystals are formed. Small domains were also found in more complex mixtures where the fatty acid is miscible in the ceramide phase, although these domains were not as regular in shape. Binary...

Joke A. Bouwstra

Papers

Model Membranes Prepared with Ceramide EOS, Cholesterol and Free Fatty Acids Form a Unique Lamellar Phase

Efficient Eradication of Established Tumors in Mice with Cationic Liposome-Based Synthetic Long-Peptide Vaccines

Thermal analysis of water in p(HEMA) hydrogels

Impact-insertion applicator improves reliability of skin penetration by solid microneedle arrays.

AFM Study of Lipid Monolayers: III. Phase Behavior of Ceramides, Cholesterol and Fatty Acids