Biologic products are large molecules such as proteins, peptides, nucleic acids, etc., which have already produced many new drugs for clinical use in the last decades. Due to the inherent challenges faced by biologics after oral administration (e.g., acidic stomach pH, digestive enzymes, and limited permeation through the gastrointestinal tract), several alternative routes of administration have been investigated to enable sufficient drug absorption into systemic circulation. This review describes the buccal, sublingual, pulmonary, and transdermal routes of administration for biologics with relevant details of the respective barriers. While all these routes avoid transit through the gastrointestinal tract, each has its own strengths and weaknesses that may be optimal for specific classes of compounds. Buccal and sublingual delivery enable rapid drug uptake through a relatively permeable barrier but are limited by small epithelial surface area, stratified epithelia, and the practical complexities of maintaining a drug delivery system in the mouth. Pulmonary delivery accesses the highly permeable and large surface area of the alveolar epithelium but must overcome the complexities of safe and effective delivery to the alveoli deep in the lung. Transdermal delivery offers convenient access to the body for extended-release delivery via the skin surface but requires the use of novel devices and formulations to overcome the skin's formidable stratum corneum barrier. New technologies and strategies advanced to overcome these challenges are reviewed, and critical views in future developments of each route are given.

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Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD-affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored.

Several single nucleotide variants (SNVs) in low-density lipoprotein receptor-related protein 6 (Lrp6) cause neural tube defects (NTDs) in mice. We therefore examined LRP6 in 192 unrelated infants from California with the NTD, spina bifida, and found four heterozygous missense SNVs, three of which were predicted to be deleterious, among NTD cases and not in 190 ethnically matched non-malformed controls. Parents and siblings could not be tested because of the study design. Like Cd and rs mouse variants, the p.Tyr544Cys Lrp6 protein failed to bind the chaperone protein MESD and impaired Lrp6 subcellular localization to the plasma membrane of MDCK II cells. Only the p.Tyr544Cys Lrp6 variant down-regulated canonical Wnt signaling in a TopFlash luciferase reporter in vitro assay. In contrast, three Lrp6 mutants (p.Ala3Val, p.Tyr544Cys and p.Arg1574Leu) increased non-canonical Wnt/PCP signaling in an Ap1-luciferase assay. Thus, LRP6 variants outside of YWTD-repeats could potentially predispose embryos to NTDs, while Lrp6 modulation of Wnt/PCP signaling would be more essential than its canonical pathway role in neural tube closure.

Background Valproic acid (VPA) is a commonly prescribed drug for those affected by epilepsy and bipolar disorders. VPA has a well known teratogenic potential, causing a variety of birth defects including neural tube defects (NTDs) and other congenital malformations, when women are treated with this medication during pregnancy. Unfortunately, the mechanism by which VPA is teratogenic remains unknown, although a range of potential mechanisms including histone deacetylase inhibition and folate antagonism have been proposed. The latter is of considerable importance, as clinicians need to know if additional folate supplements can prevent VPA-induced defects. Methods We herein approach this question experimentally, using enzyme-linked immunosorbent assay assays and cell culture modeling, to demonstrate that VPA serves as a noncompetitive inhibitor of the high affinity folate receptors. Results Binding affinities experimentally determined through enzyme-linked immunosorbent assay assays indicate that VPA serves as a noncompetitive substrate that can lessen the ability of the three primary folate forms to bind to the high affinity folate receptors. Tests in HEK293T cells indicate that the membrane-bound folate receptors of VPA treated cells bind significantly lower amounts of folic acid than do untreated cells. Conclusion If these data translate to the overall transport and subsequent bioavailability of folates, noncompetitive inhibition of the folate receptors by VPA may serve to lower the bioavailable folates in VPA treated mothers. This represents a novel mechanism by which in utero VPA exposure could be disrupting developmental processes by noncompetitively binding to the folate receptors during embryogenesis, thus inducing the wide range of defects seen in babies born to VPA treated mothers.