Spatiotemporal dynamics of microscopic biological barrier visualized by electric-double-layer modulation imaging.

Live-cell label-free imaging of a microscopic biological barrier, generally referred to as 'tight junction', was realized by a recently developed electric-double-layer modulation imaging (EDLMI). The method allowed quantitative imaging of barrier integrity in real time, thus being an upper compatible of transepithelial electrical resistance (TEER) which is a conventional standard technique to evaluate spatially averaged barrier integrity. We demonstrate that the quantitative and real-time imaging capability of EDLMI unveils fundamental dynamics of biological barrier, some of which are totally different from conventional understandings.

Absorption enhancement of peach kernel oil on hydroxysafflor yellow A in safflower extracts and its mechanisms.

Carthamus tinctorius L. (Safflower) is extensively used as a functional food and herbal medicine, with its application closely associated with hydroxysafflor yellow A (HSYA). However, the low oral bioavailability of HSYA in safflower extract (SFE) limits its health benefits and application. Our study found that co-administration of 250, 330, and 400 mg/kg peach kernel oil (PKO) increased the oral bioavailability of HSYA in SFE by 1.99-, 2.11-, and 2.49-fold, respectively. The enhanced bioavailability is attributed to improved lipid solubility and intestinal permeability of HSYA in SFE due to PKO. PKO is believed to modify membrane fluidity and tight junctions, increase paracellular penetration, and inhibit the expression and function of P-glycoprotein, enhancing the transcellular transport of substrates. These mechanisms suggest that PKO is an effective absorption enhancer. Our findings provide valuable insights for developing functional foods with improved bioavailability.

Validation of the Absorption-Enhancing Ability of Oligoarginines Grafted onto a Backbone of Hyaluronic Acid through Animal Studies from Rodents to Primates.

The purpose of our research is to develop functional additives that enhance mucosal absorption of biologics, such as peptide/protein and antibody drugs, to provide their non-to-poor invasive dosage forms self-managed by patients. Our previous in vivo and in vitro studies demonstrated that the intranasal absorption of biologics in mice was significantly improved when coadministered with oligoarginines anchored chemically to hyaluronic acid via a glycine spacer, presumably through syndecan-4-mediated macropinocytosis under activation by oligoarginines. The present mouse experiments first revealed that diglycine-L-tetraarginine-linked hyaluronic acid significantly enhanced the intranasal absorption of sulpiride, which is a poor-absorptive organic compound with a low molecular weight. However, similar enhancement was not observed for levofloxacin, which has a similarly low molecular weight but is a well-absorptive organic compound, probably because its absorption was mostly dominated by passive diffusion. The subsequent monkey experiments revealed that there was no species difference in the absorption-enhancing ability of diglycine-L-tetraarginine-linked hyaluronic acid for not only organic compounds but also biologics. This was presumably because the expression levels of endocytosis-associated membrane proteins on the nasal mucosa in monkeys were almost equivalent to those in mice, and poorly membrane-permeable/membrane-impermeable drugs were mainly absorbed via syndecan-4-mediated macropinocytosis, regardless of animal species. Drug concentrations in the brain assessed in mice and monkeys and those in the cerebral spinal fluids (CSFs) assessed in monkeys indicated that drugs would be delivered from the systemic circulation to the central nervous system by crossing the blood-brain and the blood-CSF barriers under coadministration with the hyaluronic acid derivative. In line with our original hypothesis, this new set of data supported that our oligoarginine-linked hyaluronic acid would locally perform on the mucosal surface and enhance the membrane permeation of drugs under its colocalization.

Effect of Tight Junction-Modulating FCIGRL-Modified Peptides on the Intestinal Absorption of Doxorubicin in Rats.

Doxorubicin is a potent chemotherapy drug, but its oral bioavailability is limited due to its low membrane permeability. Thus, absorption enhancers such as zonula occludens toxin and its six-mer fragment, FCIGRL, have been studied to address this issue. This study aimed to evaluate the effectiveness of four peptides (Pep1, Pep2, Pep3, and Pep4) derived from FCIGRL and investigate the changes in the absorption of doxorubicin, to propose an absorption enhancer for doxorubicin. Pep1 is a modified version of FCIGRL in which the hydroxyl group at the C-terminus is replaced with an amino group. Pep2 is a modified Pep1 in which cysteine is replaced with N3-substituted dipropionic acid. Pep3 and Pep4 are Pep2-modified homodimers. Pharmacokinetic analysis was performed in rats after the intraduodenal administration of doxorubicin solutions containing each FCIGRL-modified peptide and the stabilizer levan or benzalkonium chloride (BC). The results showed that Pep3 and Pep4 administered with levan each significantly increased the intestinal absorption of doxorubicin, as did Pep2 administered with levan/BC. In particular, 10 mg·kg-1 of Pep4 with levan significantly increased the area under the curve (AUC)0-240min of doxorubicin by 2.38-fold (p < 0.01) and the peak concentration (Cmax) by 3.30-fold (p < 0.01) compared to the control solution. The study findings indicate that Pep2, Pep3, and primarily Pep4 are novel absorption enhancers that can open tight junctions for doxorubicin, and the effectiveness of the peptides was directly affected by the presence of levan or levan/BC.

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-ß-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-ß-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

Absorption enhancer approach for protein delivery by various routes of administration: a rapid review.

As bioactive molecules, peptides and proteins are essential in living organisms, including animals and humans. Defects in their function lead to various diseases in humans. Therefore, the use of proteins in treating multiple diseases, such as cancers and hepatitis, is increasing. There are different routes to administer proteins, which have limitations due to their large and hydrophilic structure. Another limitation is the presence of biological and lipophilic membranes that do not allow proteins to pass quickly. There are different strategies to increase the absorption of proteins from these biological membranes. One of these strategies is to use compounds as absorption enhancers. Absorption enhancers are compounds such as surfactants, phospholipids and cyclodextrins that increase protein passage through the biological membrane and their absorption by different mechanisms. This review focuses on using other absorption enhancers and their mechanism in protein administration routes.

Chitooligosaccharide reconstitutes intestinal mucus layer to improve oral absorption of water-soluble drugs.

Intestinal mucus is a complex natural hydrogel barrier with unique physical properties that impede the absorption of various oral drugs. Both washout from the upper water layer and the physical resistance of the mucus layer particularly affect bioavailability of, especially, highly water-soluble molecules. One potential strategy for designing pharmaceutical formulations is to add absorption enhancers (AEs). However, there are few reports of AEs that work on mucus and their underlying mechanisms, leading to imprecise application. In this study, we investigated chitooligosaccharide (COS) as a safe, low-cost, and effective oral drug AE. We revealed the hydrodynamic law of interaction between COS and the intestinal mucus layer, which was associated with absorption benefiting mucus structural reconstruction. Based on this, we designed a translational strategy to improve the bioavailability of a group of soluble oral drugs by drinking COS solution before administration. Moreover, this research is expected to expand its application scenario by reducing drug dosage such as avoiding gastro-intestinal irritation and slowing veterinary antibiotic resistance.

Pharmacologic Comparison of High-Dose Hesperetin and Quercetin on MDCK II Cell Viability, Tight Junction Integrity, and Cell Shape.

The modulation of tight junction (TJ) integrity with small molecules is important for drug delivery. High-dose baicalin (BLI), baicalein (BLE), quercetin (QUE), and hesperetin (HST) have been shown to open TJs in Madin-Darby canine kidney (MDCK) II cells, but the mechanisms for HST and QUE remain unclear. In this study, we compared the effects of HST and QUE on cell proliferation, morphological changes, and TJ integrity. HST and QUE were found to have opposing effects on the MDCK II cell viability, promotion, and suppression, respectively. Only QUE, but not HST, induced a morphological change in MDCK II into a slenderer cell shape. Both HST and QUE downregulated the subcellular localization of claudin (CLD)-2. However, only QUE, but not HST, downregulated CLD-2 expression. Conversely, only HST was shown to directly bind to the first PDZ domain of ZO-1, a key molecule to promote TJ biogenesis. The TGFß pathway partially contributed to the HST-induced cell proliferation, since SB431541 ameliorated the effect. In contrast, the MEK pathway was not involved by both the flavonoids, since U0126 did not revert their TJ-opening effect. The results offer insight for using HST or QUE as naturally occurring absorption enhancers through the paracellular route.

Intestinal absorptivity-increasing effects of sodium N-[8-(2-hydroxybenzoyl)amino]-caprylate on food-derived bioactive peptide.

Delivering bioactive peptides orally is hampered by poor absorption across the gastrointestinal barrier. Using the walnut-derived peptide PW5, PPKNW, we explored whether coformulation of peptides with absorption enhancer sodium N-[8-(2-hydroxybenzoyl)aminocaprylate] (SNAC) could improve the intestinal absorption of orally-administered bioactive peptides. Herein, the application of SNAC enhanced the absorption efficiency of PW5 in a non-everted gut sac model. Particle size distribution (1 027.8 ± 6.74 nm) and zeta potential (-2.89 ± 0.07 mV) of the PW5-SNAC complex were significantly greater than that of individual PW5 and SNAC. Scanning electron microscopy revealed that SNAC application could aggravate the surface roughness and reduce the compact structure of PW5. It further showed that PW5 and SNAC binds through an endothermic process underpinned by hydrogen bond and van der Waals forces and that SNAC could bound primarily to the internal calyx of PW5. These findings are helpful for the effective delivery of bioactive peptides.

Oral Absorption of Middle-to-Large Molecules and Its Improvement, with a Focus on New Modality Drugs.

To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus® tablets and Mycapssa® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption.

Strategies for enhancing the oral bioavailability of cannabinoids.

INTRODUCTION: Oral administration of cannabinoids is a convenient route of administration in many cases. To enhance the poor and variable bioavailability of cannabinoids, selected strategies utilizing proper delivery systems have been designed. Low solubility in the GI aqueous media is the first and most critical barrier. Thereafter, cannabinoids can reach the systemic blood circulation via the portal vein that is associated with significant hepatic first pass metabolism (FPM) or bypass it via lymphatic absorption. AREAS COVERED: The solubility obstacle of cannabinoids is mainly addressed with lipid-based formulations such as self-nanoemulsifying drug delivery systems (SNEDDS). Certain lipids are used to overcome the solubility issue. Surfactants and other additives in the formulation have additional impact on several barriers, including dictating the degree of lymphatic bioavailability and hepatic FPM. Gastro-retentive formulation is also plausible. EXPERT OPINION: Comparison of the role of the same SNEDDS formulation, cyclosporine vs. cannabinoids, when used to elevate the oral bioavailability of different compounds, is presented. It illustrates some similarities and major mechanistic differences obtained by the same SNEDDS. Thus, the different influence over the absorption pathway illuminates the importance of understanding the absorption mechanism and its barriers to properly select appropriate strategies to achieve enhanced oral bioavailability.

Effect of Different Absorption Enhancers on the Nasal Absorption of Nalmefene Hydrochloride.

The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-ß-D-maltoside (DDM), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-ß-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.

Advances in oral absorption of polysaccharides: Mechanism, affecting factors, and improvement strategies.

Polysaccharides have been widely used as biomaterials and drugs after oral administration due to their suitable physicochemical properties, good bioactivities and low toxicities. However, studies on their pharmacokinetics and absorption mechanism after oral administration are significantly restricted by the lack of polysaccharide detection methods. With the advancement of polysaccharide detection technologies such as immunoassays, fluorescent and isotopic labelling, the oral pharmacokinetics of polysaccharides have gradually been revealed. Here, paracellular pathway, transcellular pathways and M cell-mediated transport were analysed as mechanisms for oral absorption. The potential factors affecting the oral absorption of polysaccharides, including their charge, molecular weight, spatial structure and dose, as well as the species and physiological state of organisms, were analysed. Based on the absorption mechanism and influencing factors, we look forward to further investigating possible strategies for improving the oral absorption of polysaccharides.

Acquisition of absorption-enhancing abilities of cationic oligopeptides with short chain arginine residues through conjugation to hyaluronic acid.

Cell-penetrating peptides such as oligoarginines are one of promising tools that improve mucosal absorption of poorly membrane-permeable biologics. We have already demonstrated that conjugation of L-octaarginine to hyaluronic acid via a tetraglycine spacer resulted in a 3-fold enhancement of nasal absorption of somatropin (Mw: ca. 22.1 kDa) in mice when compared with the unmodified peptide. Here, we evaluated absorption-enhancing abilities and safety profiles of oligopeptides with short chain arginine residues conjugated to hyaluronic acid. Somatropin absorption was hardly ever enhanced by diglycine-L-tetraarginine. The peptide acquired the absorption-enhancing ability through the conjugation; however, it disappeared when arginine residues were halved. In vivo data were consistent to in vitro cellular uptake of somatropin. When somatropin was substituted with exendin-4 (Mw: ca. 4.2 kDa), cellular uptake was significantly enhanced by diglycine-L-diarginine conjugated to hyaluronic acid under comparison with the unmodified peptide. The conjugate also exhibited the enhancement ability in mice, as observed for hyaluronic acid derivatives with four and more arginine residues. Another cell studies revealed that oligoarginine-linked hyaluronic acid tended to be less toxic as arginine residues were reduced. Results indicated that diglycine-L-tetraarginine-linked hyaluronic acid was the most suitable candidate as an absorption enhancer whose Mw-independent enhancement ability and safety were well-balanced.

Utilization of Sodium Nitroprusside as an Intestinal Permeation Enhancer for Lipophilic Drug Absorption Improvement in the Rat Proximal Intestine.

As advanced synthetic technology has enabled drug candidate development with complex structure, resulting in low solubility and membrane permeability, the strategies to improve poorly absorbed drug bioavailability have attracted the attention of pharmaceutical companies. It has been demonstrated that nitric oxide (NO), a vital signaling molecule that plays an important role in various physiological systems, affects intestinal drug absorption. However, NO and its oxidants are directly toxic to the gastrointestinal tract, thereby limiting their potential clinical application as absorption enhancers. In this study, we show that sodium nitroprusside (SNP), an FDA-approved vasodilator, enhances the intestinal absorption of lipophilic drugs in the proximal parts of the small intestine in rats. The SNP pretreatment of the rat gastrointestinal sacs significantly increased griseofulvin and flurbiprofen permeation in the duodenum and jejunum but not in the ileum and colon. These SNP-related enhancement effects were attenuated by the co-pretreatment with dithiothreitol or c-PTIO, an NO scavenger. The permeation-enhancing effects were not observed in the case of antipyrine, theophylline, and propranolol in the duodenum and jejunum. Furthermore, the SNP treatment significantly increased acidic glycoprotein release from the mucosal layers specifically in the duodenum and jejunum but not in the ileum and colon. These results suggest that SNP increases lipophilic drug membrane permeability specifically in the proximal region of the small intestine through disruption of the mucosal layer.

Spermine with Sodium Taurocholate Enhances Pulmonary Absorption of Macromolecules in Rats.

The improvement effect of the combined use of spermine (SPM), a polyamine, with sodium taurocholate (STC) on the pulmonary drug absorption was investigated utilizing poorly absorbable drugs with various molecular sizes in rats. The pulmonary absorption of rebamipide, a low molecular but poorly absorbable drug after oral administration, was significantly improved by the combined use of SPM with STC (SPM-STC formulation), while poly- L-lysine did not show a significant change in rebamipide absorption from the lungs. Furthermore, the safety of the SPM-STC formulation for the lungs was assessed in rats by the histopathological study and any local toxicity was not observed while poly-L-lysine, a typical chemical causing the toxicity for the epithelial cells, provided several histopathological changes. In addition, the SPM-STC formulation significantly improved the pulmonary absorption of fluorescein isothiocyanate dextran 4 (FD-4, Mw ca 4000) and interferon-α (IFN-α, Mw ca 25,000) as well. Our present results clearly indicated that the SPM-STC formulation significantly improved the pulmonary absorption of poorly absorbable small and large molecular drugs without any harmful effects on the lungs. Therefore, the SPM-STC formulation would be a useful one for the pulmonary absorption of drugs, specifically macromolecular ones, which are very difficult to be absorbed after oral administration.

NMR-Guided Repositioning of Non-Steroidal Anti-Inflammatory Drugs into Tight Junction Modulators.

Bioavailability is a major bottleneck in the clinical application of medium molecular weight therapeutics, including protein and peptide drugs. Paracellular transport of these molecules is hampered by intercellular tight junction (TJ) complexes. Therefore, safe chemical regulators for TJ loosening are desired. Here, we showed a potential application of select non-steroidal anti-inflammatory drugs (NSAIDs) as TJ modulators. Based on our previous observation that diclofenac and flufenamic acid directly bound various PDZ domains with a broad specificity, we applied solution nuclear magnetic resonance techniques to examine the interaction of other NSAIDs and the first PDZ domain (PDZ1) of zonula occludens (ZO)-1, ZO-1(PDZ1). Inhibition of ZO-1(PDZ1) is expected to provide loosening of the epithelial barrier function because the domain plays a crucial role in maintaining TJ integrity. Accordingly, diclofenac and indomethacin were found to decrease the subcellular localization of claudin (CLD)-2 but not occludin and ZO-1 at the apicolateral intercellular compartment of Madin-Darby canine kidney (MDCK) II cells. These NSAIDs exhibited 125-155% improved paracellular efflux of fluorescein isothiocyanate insulin for the Caco-2 cell monolayer. We propose that these NSAIDs can be repurposed as drug absorption enhancers for peptide drugs.

Enhancing CO2 utilization by a physical absorption-based technique in microalgae culture.

Carbon dioxide supplementation is significant for cell growth in autotrophic cultures of microalgae. However, the CO2 utilization efficiency is quite low in most processes. Aimed at this problem, six kinds of physical absorption enhancers were investigated to enhance the biological carbon sequestration of microalgae. By the addition of a small amount of CO2 absorption enhancer, the total inorganic carbon concentration of the medium was significantly increased. In addition, the biomass productivity of Scenedesmus dimorphus was maximally increased by 63% by the addition of propylene carbonate in flask cultures. In cultures using an air-lift photobioreactor equipped with a pH-feedback control system to supply CO2, the CO2 consumption was maximally reduced by 71% with added polyethylene glycol dimethyl ether. This study indicates that the incorporation of physical absorption enhancers could be a promising approach to overcome the problems of low CO2 utilization efficiency and high carbon source cost in algal biomass production.

The efficiency and mechanism of a new absorption enhancer, malic acid, for enhancing the oral bioavailability of docetaxel.

This study investigated the efficiency and the related mechanisms of a new absorption enhancer, DL-malic acid (MA), on the oral bioavailability of docetaxel (DTX). Polyethylene glycol polycarbonate (PEG-PCL) modified liposomes (PLip) were prepared for DTX, and incorporated into the pH-sensitive microspheres (MS) with sustained release. MA decreased the transepithelial electrical resistance (TEER) across a Caco-2 cell monolayer by 20% and 57% after 2 and 3 h of co-incubation with DTX-PLip and the cells, respectively, indicating that MA could open tight junctions but not instantaneously. After long enough exposure (4 h) of MA to the small intestine of rats, only the absorption rate constant (ka) of DTX-PLip, but not Duopafei®, was increased, which could be related to the intestinal mucosal permeability of DTX. After co-administration in rats, MA significantly enhanced the oral bioavailability of DTX in DTX-PLip-MS from 44.67% to 81.27%, rather than DTX-PLip and Duopafei®, which could be related to the prolonged intestinal retention time of DTX-PLip via the MS and the promoted drug intercellular transport by MA. The absorption-enhancing effects of MA on DTX-PLip-MS were further confirmed by in vivo imaging. The above findings suggest that MA served as a new and efficient absorption enhancer for DTX-PLip-MS.HIGHlIGHTSIn this study, malic acid as a new absorption enhancer for DTX in polymer-liposome (PLip) embedded in pH-sensitive microspheres (MS) was found for the first time.The malic acid could significantly enhance oral bioavailability of DTX in DTX-PLip-MS (from 44.67 % to 81.27%) rather than Duopafei® and DTX-PLip after co-administration.The absorption enhancement may be closely related to the intestinal retention time and mucosal permeability.These findings will provide an important reference for the study of absorption enhancers for promoting intercellular insoluble drug transport.

Novel Insights to Enhance Therapeutics With Acyclovir in the Management of Herpes Simplex Encephalitis.

Acyclovir is an antiviral drug poorly absorbed in the gastrointestinal tract due to its hydrophilicity, with low oral bioavailability (~20%). Although acyclovir is prescribed in the management of herpes simplex encephalitis (HSE), the disease has a poor prognosis, particularly if the treatment is delayed, reaching mortality rates of 70% if left untreated. Thus, high acyclovir doses are administered by intravenous (IV) infusion, usually at a dosage of 10 mg kg-1 8-hourly in adults with normal renal function. However, the mortality related to HSE treated with acyclovir remains high (~20%) and permanent sequelae are commonly reported after 1 year (~50%). This review analyzed clinical trials following IV acyclovir administration. Novel insights aiming to improve drug bioavailability were reviewed, including acyclovir or its prodrugs, leading to the systemic distribution of the drug or drug targeting. Much research effort has been made to improve antiviral therapy, searching for delivery systems increasing acyclovir bioavailability by non-invasive pathways, such as oral and nasal pathways, or parenterally administered nanotechnology-based systems leading to drug targeting. Nanocarriers administered by non-invasive pathways represent feasible alternatives to treat HSE, even though not be industrially manufactured yet.