Peptides as Pharmacological Carriers to the Brain: Promises, Shortcomings and Challenges.

Central nervous system (CNS) diseases are among the most difficult to treat, mainly because the vast majority of the drugs fail to cross the blood-brain barrier (BBB) or to reach the brain at concentrations adequate to exert a pharmacological activity. The obstacle posed by the BBB has led to the in-depth study of strategies allowing the brain delivery of CNS-active drugs. Among the most promising strategies is the use of peptides addressed to the BBB. Peptides are versatile molecules that can be used to decorate nanoparticles or can be conjugated to drugs, with either a stable link or as pro-drugs. They have been used to deliver to the brain both small molecules and proteins, with applications in diverse therapeutic areas such as brain cancers, neurodegenerative diseases and imaging. Peptides can be generally classified as receptor-targeted, recognizing membrane proteins expressed by the BBB microvessels (e.g., Angiopep2, CDX, and iRGD), "cell-penetrating peptides" (CPPs; e.g. TAT47-57, SynB1/3, and Penetratin), undergoing transcytosis through unspecific mechanisms, or those exploiting a mixed approach. The advantages of peptides have been extensively pointed out, but so far few studies have focused on the potential negative aspects. Indeed, despite having a generally good safety profile, some peptide conjugates may display toxicological characteristics distinct from those of the peptide itself, causing for instance antigenicity, cardiovascular alterations or hemolysis. Other shortcomings are the often brief lifetime in vivo, caused by the presence of peptidases, the vulnerability to endosomal/lysosomal degradation, and the frequently still insufficient attainable increase of brain drug levels, which remain below the therapeutically useful concentrations. The aim of this review is to analyze not only the successful and promising aspects of the use of peptides in brain targeting but also the problems posed by this strategy for drug delivery.

Mitochondrial channels: ion fluxes and more.

The field of mitochondrial ion channels has recently seen substantial progress, including the molecular identification of some of the channels. An integrative approach using genetics, electrophysiology, pharmacology, and cell biology to clarify the roles of these channels has thus become possible. It is by now clear that many of these channels are important for energy supply by the mitochondria and have a major impact on the fate of the entire cell as well. The purpose of this review is to provide an up-to-date overview of the electrophysiological properties, molecular identity, and pathophysiological functions of the mitochondrial ion channels studied so far and to highlight possible therapeutic perspectives based on current information.

Targeting Pancreatic Ductal Adenocarcinoma (PDAC).

Pancreatic cancers are among the most ominous, and among the most studied. Their complexities have provided ample material for a huge investigative effort, which is briefly surveyed in this review. Eradication by surgery has proven extremely difficult, and a successful chemotherapeutic approach is desperately needed. Treatment with "traditional" anticancer drugs, such as benchmark gemcitabine or the current standard-of-care FOLFIRINOX quaternary combination increase the mean overall survival by only a few months and often leads to chemoresistance. Much work is therefore currently devoted to potentiating our pharmacological weapons by accurate targeting and, in particular, by acting on the dense tumoral stroma, a distinctive feature of PDAC accounting for much of the therapeutic difficulty. We give an overview of recent developments, touching on the major aspects of PDAC physiology and biochemistry, currently-used and experimental drugs, and targeting technologies under development. A few papers are discussed in some detail to help provide a sense of how the field is moving.

Synthesis and cellular effects of a mitochondria-targeted inhibitor of the two-pore potassium channel TASK-3.

The two-pore potassium channel TASK-3 has been shown to localize to both the plasma membrane and the mitochondrial inner membrane. TASK-3 is highly expressed in melanoma and breast cancer cells and has been proposed to promote tumor formation. Here we investigated whether pharmacological modulation of TASK-3, and specifically of mitochondrial TASK-3 (mitoTASK-3), had any effect on cancer cell survival and mitochondrial physiology. A novel, mitochondriotropic version of the specific TASK-3 inhibitor IN-THPP has been synthesized by addition of a positively charged triphenylphosphonium moiety. While IN-THPP was unable to induce apoptosis, mitoIN-THPP decreased survival of breast cancer cells and efficiently killed melanoma lines, which we show to express mitoTASK-3. Cell death was accompanied by mitochondrial membrane depolarization and fragmentation of the mitochondrial network, suggesting a role of the channel in the maintenance of the correct function of this organelle. In accordance, cells treated with mitoIN-THPP became rapidly depleted of mitochondrial ATP which resulted in activation of the AMP-dependent kinase AMPK. Importantly, cell survival was not affected in mouse embryonic fibroblasts and the effect of mitoIN-THPP was less pronounced in human melanoma cells stably knocked down for TASK-3 expression, indicating a certain degree of selectivity of the drug both for pathological cells and for the channel. In addition, mitoIN-THPP inhibited cancer cell migration to a higher extent than IN-THPP in two melanoma cell lines. In summary, our results point to the importance of mitoTASK-3 for melanoma cell survival and migration.

Small-Molecule Modulators of Mitochondrial Channels as Chemotherapeutic Agents.

Ion channels residing in the inner (IMM) and outer (OMM) mitochondrial membranes are emerging as noteworthy pharmacological targets in oncology. While these aspects have not been investigated for all of them, a role in cancer growth and/or metastasis and/or drug resistance has been shown at least for the IMM-residing Ca2+ uniporter complex and K+- selective mtKV1.3, mtIKCa, mtSKCa and mtTASK-3, and for the OMM Voltage-Dependent Anion Channel (mitochondrial porin). A special case is that of the Mitochondrial Permeability Transition Pore, a large pore which forms in the IMM of severely stressed cells, and which may be exploited to precipitate the death of cancerous cells. Here we briefly discuss the oncological relevance of mitochondria and their channels, and summarize the methods that can be adopted to selectively target these intracellular organelles. We then present an updated list of known mitochondrial channels, and review the pharmacology of those with proven relevance for cancer.

Pterostilbene Improves Cognitive Performance in Aged Rats: An in Vivo Study.

BACKGROUND/AIMS: Pterostilbene (Pt; trans-3,5-dimethoxy-4'-hydroxystilbene) is a natural phenol found in blueberries and grapevines. It shows remarkable biomedical activities similar to those of resveratrol. Its high bioavailability is a major advantage for possible biomedical applications. The goal of the study was to evaluate the effects of chronic pterostilbene administration on cognitive performance in aged rats with mild cognitive impairment. METHODS: 18-month-old animals were subjected to behavioral tests to establish the "baseline", then divided into treatment and control groups. The former were chronically fed Pt (22.5 mg/kg-day) for 20 consecutive days. At the end of this period all animals were tested again and sacrificed. The dentate gyrus, the hippocampus and the prefrontal and perirhinal cortices were then collected, and RT-qPCR and/or Western blot analyses were performed on a few transcripts/proteins involved in synaptic remodeling. Mitochondrial content was also assessed. RESULTS: Pt administration improved performance in behavioral tests and positively affected memory consolidation. We found increased levels of REST, PSD-95 and mitochondrial porin1 in the dentate gyrus and a positive correlation between T-maze test score and levels of cAMP responsive element binding protein (CREB) phosphorylation. CONCLUSION: These results underscore the therapeutic potential of Pt supplementation for age-related cognitive decline.

Inhibition of PI-3-K and AKT Amplifies Kv1.3 Inhibitor-Induced Death of Human T Leukemia Cells.

BACKGROUND/AIMS: We have previously shown that inhibition of the mitochondrial Kv1.3 channel results in an initial mitochondrial hyperpolarization and a release of oxygen radicals that mediate mitochondrial depolarization, cytochrome c release and death. Here, we investigated whether inhibition of Kv1.3 channels can also induce cellular resistance mechanisms that counteract the induction of cell death under certain conditions. METHODS: We treated leukemic T cells with the mitochondria-targeted Kv1.3 inhibitor PCARBTP and determined the activity of different kinases associated with cell survival including ZAP70, PI-3-K, AKT, JNK and ERK by measuring the activation-associated phosphorylation of these proteins. Furthermore, we inhibited AKT and JNK and determined the effect of PCARBTP-induced tumor cell death. RESULTS: We demonstrate that treatment of Jurkat T leukemia cells with low doses of the mitochondria-targeted inhibitor of Kv1.3 PCARBTP (0.25 µM or 1 µM) for 10 minutes induced a constitutive phosphorylation/activation of the pro-survival signaling molecules ZAP70, PI-3-K, AKT and JNK, while the phosphorylation/activation of ERK was not affected. Stimulation of Jurkat cells via the TCR/CD3 complex induced an additional activation of a similar pattern of signaling events. Higher doses of the Kv1.3 inhibitor, i.e. 10 µM PCARBTP, reduced the basal phosphorylation/activation of these signaling molecules and also impaired their activation upon stimulation via the TCR/CD3 complex. A low dose of PCARBTP, i.e. 0.25 µM PCARBTP, was almost without any effect on cell death. In contrast, concomitant inhibition of PI-3-K or AKT greatly sensitized Jurkat leukemia cells to the Kv1.3 inhibitor PCARBTP and allowed induction of cell death already at 0.25 µM PCARBTP. CONCLUSION: These studies indicate that Jurkat leukemia cells respond to low doses of the mitochondria-targeted Kv1.3 inhibitor PCARBTP with an activation of survival signals counteracting cell death. Inhibition of these T cell survival signals sensitizes leukemia cells to death induced by mitochondria-targeted Kv1.3 inhibitors. High doses of the Kv1.3 inhibitor inactivate these signals directly permitting death.

The mitochondrial permeability transition pore in AD 2016: An update.

Over the past 30years the mitochondrial permeability transition - the permeabilization of the inner mitochondrial membrane due to the opening of a wide pore - has progressed from being considered a curious artifact induced in isolated mitochondria by Ca(2+) and phosphate to a key cell-death-inducing process in several major pathologies. Its relevance is by now universally acknowledged and a pharmacology targeting the phenomenon is being developed. The molecular nature of the pore remains to this day uncertain, but progress has recently been made with the identification of the FOF1 ATP synthase as the probable proteic substrate. Researchers sharing this conviction are however divided into two camps: these believing that only the ATP synthase dimers or oligomers can form the pore, presumably in the contact region between monomers, and those who consider that the ring-forming c subunits in the FO sector actually constitute the walls of the pore. The latest development is the emergence of a new candidate: Spastic Paraplegia 7 (SPG7), a mitochondrial AAA-type membrane protease which forms a 6-stave barrel. This review summarizes recent developments of research on the pathophysiological relevance and on the molecular nature of the mitochondrial permeability transition pore. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Pharmacological targeting of ion channels for cancer therapy: In vivo evidences.

Since the discovery of the participation of various ion channels in the regulation of cell proliferation and programmed cell death two decades ago, the field exploring ion channel function in relation to cancer has undergone rapid development. Although the mechanisms accounting for the impact of ion channel modulators on cancer growth have not been fully clarified in all cases, numerous in vivo experiments targeting diverse ion channels in various cancer models illustrate the great potentiality of this approach and promote ion channels to the class of oncological targets. In the present review we give an updated overview of the field and critically discuss the promising results obtained in pre-clinical models using specific pharmacological modulators of calcium, sodium, potassium and anion-permeable ion channels, whose expression is often altered in tumor cells and tissues. The most, especially critical issues are specificity of action and side-effects. Interestingly, some of the most potent drugs are natural products, and several of the active compounds are already used in the clinic for other purposes. In these latter cases involving drug repositioning we may expect a faster progression from preclinical to clinical studies. This article is part of a Special Issue entitled: Calcium and Cell Fate. Guest Editors: Jacques Haiech, Claus Heizmann, Joachim Krebs, Thierry Capiod and Olivier Mignen.

Targeting the Potassium Channel Kv1.3 Kills Glioblastoma Cells.

BACKGROUND/AIMS: Glioblastoma (GBM) is one of the most aggressive cancers, counting for a high number of the newly diagnosed patients with central nervous system (CNS) cancers in the United States and Europe. Major features of GBM include aggressive and invasive growth as well as a high resistance to treatment. Kv1.3, a potassium channel of the shaker family, is expressed in the inner mitochondrial membrane of many cancer cells. Inhibition of mitochondrial Kv1.3 was shown to induce apoptosis in several tumor cells at doses that were not lethal for normal cells. METHODS: We investigated the expression of Kv1.3 in different glioma cell lines by immunocytochemistry, western blotting and electron microscopy and analyzed the effect of newly synthesized, mitochondria-targeted, Kv1.3 inhibitors on the induction of cell death in these cells. Finally, we performed in vivo studies on glioma bearing mice. RESULTS: Here, we report that Kv1.3 is expressed in mitochondria of human and murine GL261, A172 and LN308 glioma cells. Treatment with the novel Kv1.3 inhibitors PAPTP or PCARBTP as well as with clofazimine induced massive cell death in glioma cells, while Psora-4 and PAP-1 were almost without effect. However, in vivo experiments revealed that the drugs had no effect on orthotopic brain tumors in vivo. CONCLUSION: These data serve as proof of principle that Kv1.3 inhibitors kills GBM cells, but drugs that act in vivo against glioblastoma must be developed to translate these findings in vivo.

Potential anti-cancer activity of 7-O-pentyl quercetin: Efficient, membrane-targeted kinase inhibition and pro-oxidant effect.

Quercetin is a redox-active plant-derived flavonoid with potential anticancer effects, stemming largely from its interaction with a number of proteins, and in particular from inhibition of pro-life kinases. To improve efficacy, we reasoned that a local increase in concentration of the compound at the level of cell membranes would result in a more efficient interaction with membrane-associated signaling kinases. We report here the synthesis of all five isomeric quercetin derivatives in which an n-pentyl group was linked via an ether bond to each hydroxyl of the flavonoid kernel. This strategy proved effective in directing quercetin to cellular membranes, and revealed a remarkable dependence of the derivatives' bioactivity on the specific site of functionalization. The isomer bearing the pentyl group in position 7, Q-7P, turned out to be the most effective and promising derivative, selectively inducing apoptosis in tumoral and fast-growing cells, while sparing slow-growing, non-tumoral ones. Cytotoxicity for tumoral cells was strongly enhanced compared to quercetin itself. Q-7P induced massive ROS production, which however accounted only partially for cell death. Alterations in the levels of various signaling phospho-proteins were observed in a proteomics screen. An important contribution seems to come from inhibition of the PI3K/Akt pathway. This work opens new perspectives in developing membrane-associating, polyphenol-based anticancer agents.

Dimers of mitochondrial ATP synthase form the permeability transition pore.

Here we define the molecular nature of the mitochondrial permeability transition pore (PTP), a key effector of cell death. The PTP is regulated by matrix cyclophilin D (CyPD), which also binds the lateral stalk of the FOF1 ATP synthase. We show that CyPD binds the oligomycin sensitivity-conferring protein subunit of the enzyme at the same site as the ATP synthase inhibitor benzodiazepine 423 (Bz-423), that Bz-423 sensitizes the PTP to Ca(2+) like CyPD itself, and that decreasing oligomycin sensitivity-conferring protein expression by RNAi increases the sensitivity of the PTP to Ca(2+). Purified dimers of the ATP synthase, which did not contain voltage-dependent anion channel or adenine nucleotide translocator, were reconstituted into lipid bilayers. In the presence of Ca(2+), addition of Bz-423 triggered opening of a channel with currents that were typical of the mitochondrial megachannel, which is the PTP electrophysiological equivalent. Channel openings were inhibited by the ATP synthase inhibitor AMP-PNP (γ-imino ATP, a nonhydrolyzable ATP analog) and Mg(2+)/ADP. These results indicate that the PTP forms from dimers of the ATP synthase.

Channel formation by yeast F-ATP synthase and the role of dimerization in the mitochondrial permeability transition.

Purified F-ATP synthase dimers of yeast mitochondria display Ca(2+)-dependent channel activity with properties resembling those of the permeability transition pore (PTP) of mammals. After treatment with the Ca(2+) ionophore ETH129, which allows electrophoretic Ca(2+) uptake, isolated yeast mitochondria undergo inner membrane permeabilization due to PTP opening. Yeast mutant strains ΔTIM11 and ΔATP20 (lacking the e and g F-ATP synthase subunits, respectively, which are necessary for dimer formation) display a striking resistance to PTP opening. These results show that the yeast PTP originates from F-ATP synthase and indicate that dimerization is required for pore formation in situ.

Cytotoxicity of mitochondria-targeted resveratrol derivatives: interactions with respiratory chain complexes and ATP synthase.

We recently reported that mitochondria-targeted derivatives of resveratrol are cytotoxic in vitro, selectively inducing mostly necrotic death of fast-growing and tumoral cells when supplied in the low µM range (N. Sassi et al., Curr. Pharm. Des. 2014). Cytotoxicity is due to H2O2 produced upon accumulation of the compounds into mitochondria. We investigate here the mechanisms underlying ROS generation and mitochondrial depolarization caused by these agents. We find that they interact with the respiratory chain, especially complexes I and III, causing superoxide production. "Capping" free hydroxyls with acetyl or methyl groups increases their effectiveness as respiratory chain inhibitors, promoters of ROS generation and cytotoxic agents. Exposure to the compounds also induces an increase in the occurrence of short transient [Ca(2+)] "spikes" in the cells. This increase is unrelated to ROS production, and it is not the cause of cell death. These molecules furthermore inhibit the F0F1 ATPase. When added to oligomycin-treated cells, the acetylated/methylated ones cause a recovery of the cellular oxygen consumption rates depressed by oligomycin. Since a protonophoric futile cycle which might account for the uncoupling effect is impossible, we speculate that the compounds may cause the transformation of the ATP synthase and/or respiratory chain complex(es) into a conduit for uncoupled proton translocation. Only in the presence of excess oligomycin the most effective derivatives appear to induce the mitochondrial permeability transition (MPT) within the cells. This may be considered to provide circumstantial support for the idea that the ATP synthase is the molecular substrate for the MPT pore.

Synthesis and Evaluation as Prodrugs of Hydrophilic Carbamate Ester Analogues of Resveratrol.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is an unfulfilled promise for health care: its exploitation is hindered by rapid conjugative metabolism in enterocytes and hepatocytes; low water solubility is a serious practical problem. To advantageously modify the physicochemical properties of the compound we have developed prodrugs in which all or part of the hydroxyl groups are linked via an N-monosubstituted carbamate ester bond to promoieties derived from glycerol or galactose, conferring higher water solubility. Kinetic studies of hydrolysis in aqueous solutions and in blood indicated that regeneration of resveratrol takes place in an appropriate time frame for delivery via oral administration. Despite their hydrophilicity some of the synthesized compounds were absorbed in the gastrointestinal tract of rats. In these cases the species found in blood after administration of a bolus consisted mainly of partially deprotected resveratrol derivatives and of the products of their glucuronidation, thus providing proof-of-principle evidence of behavior as prodrugs. The soluble compounds largely reached the lower intestinal tract. Upon administration of resveratrol, the major species found in this region was dihydroresveratrol, produced by enzymes of the intestinal flora. In experiments with a fully protected (trisubstituted) deoxygalactose containing prodrug, the major species were the prodrug itself and partially deprotected derivatives, along with small amounts of dihydroresveratrol. We conclude that the N-monosubstituted carbamate moiety is suitable for use in prodrugs of polyphenols.

N-Monosubstituted Methoxy-oligo(ethylene glycol) Carbamate Ester Prodrugs of Resveratrol.

Resveratrol is a natural polyphenol with many interesting biological activities. Its pharmacological exploitation in vivo is, however, hindered by its rapid elimination via phase II conjugative metabolism at the intestinal and, most importantly, hepatic levels. One approach to bypass this problem relies on prodrugs. We report here the synthesis, characterization, hydrolysis, and in vivo pharmacokinetic behavior of resveratrol prodrugs in which the OH groups are engaged in an N-monosubstituted carbamate ester linkage. As promoiety, methoxy-oligo(ethylene glycol) groups (m-OEG) (CH3-[OCH2CH2]n-) of defined chain length (n = 3, 4, 6) were used. These are expected to modulate the chemico-physical properties of the resulting derivatives, much like longer poly(ethylene glycol) (PEG) chains, while retaining a relatively low MW and, thus, a favorable drug loading capacity. Intragastric administration to rats resulted in the appearance in the bloodstream of the prodrug and of the products of its partial hydrolysis, confirming protection from first-pass metabolism during absorption.

A preliminary fastview of mitochondrial protein profile from healthy and type 2 diabetic subjects.

Type 2 diabetes results from the development of insulin resistance and a concomitant impairment of insulin secretion. Mitochondrial dysfunctions are thought to be the major contributor to the development of various pathologies, including type 1 and type 2 diabetes mellitus. Mitochondrial oxidative stress has been reported in models of both type 1 and type 2 diabetes mellitus and may play a central role in mitochondrial dysfunction. In the present study, we investigated the occurrence of protein alterations, due to the presence of type 2 diabetes, in mitochondria isolated from human peripheral blood mononuclear cells (PBMCs] by matrix-assisted laser desorp- tion/ionization mass spectrometry (MALDI-MS]. PBMCs may be suitable for this investigation because they have insulin receptors that quickly respond to changes in insulin concentration, and in the presence of insulin rapidly increase their rates of glucose utiliza- tion. In the presence of insulin-resistance conditions, such as type 2 diabetes mellitus, this mechanism is altered and the glycation of cytoplasmic as well as mitochondrial proteins may plausibly appear. Therefore, PBMCs may be useful tools to verify modifications or altered expression of mitochondrial proteins. Human mitochondria were obtained from 32 subjects, 16 healthy controls and 16 type 2 diabetic patients. Two different methods for mitochondria isolation and purification were employed and compared. Some proteins have been found to be differently expressed in the two groups of subjects under investigation and can be classified into two sets: i.e. proteins related to ATP synthase [e.g. 6.8kDa mitochondrial proteolipid [MLQ]; ATP-CF6 [m/z 12,597)] and proteins related to cell proliferation and apoptosis [e.g. TIMM9 [m/z 10,378); Bcl-2-like protein 2 (m/z20,742)].

New water-soluble carbamate ester derivatives of resveratrol.

Low bioavailability severely hinders exploitation of the biomedical potential of resveratrol. Extensive phase-II metabolism and poor water solubility contribute to lowering the concentrations of resveratrol in the bloodstream after oral administration. Prodrugs may provide a solution-protection of the phenolic functions hinders conjugative metabolism and can be exploited to modulate the physicochemical properties of the compound. We report here the synthesis and characterization of carbamate ester derivatives of resveratrol bearing on each nitrogen atom a methyl group and either a methoxy-poly(ethylene glycol)-350 (mPEG-350) or a butyl-glucosyl promoiety conferring high water solubility. Ex vivo absorption studies revealed that the butyl-glucosyl conjugate, unlike the mPEG-350 one, is able to permeate the intestinal wall. In vivo pharmacokinetics confirmed absorption after oral administration and showed that no hydrolysis of the carbamate groups takes place. Thus, sugar groups can be attached to resveratrol to obtain soluble derivatives maintaining to some degree the ability to permeate biomembranes, perhaps by facilitated or active transport.

Cytotoxicity of a mitochondriotropic quercetin derivative: mechanisms.

The mitochondriotropic compound 7-O-(4-triphenylphosphoniumbutyl)quercetin iodide (Q-7BTPI) in the µM concentration range caused necrotic death of cultured cells by acting as a prooxidant, with generation of superoxide anion in the mitochondria. Externally added membrane-permeating superoxide dismutase or catalase largely prevented death. Rescue by permeant catalase indicates that the toxicant is H(2)O(2), or reactive species derived from it. Rescue by permeant dismutase suggests the possibility of a chain mechanism of H(2)O(2) production, in which dismutation of superoxide constitutes a termination step. Oxidative stress was due to the presence of free phenolic hydroxyls and to accumulation in mitochondria, since the analogous mitochondriotropic per-O-methylated compound -3,3',4',5-tetra-O-methyl,7-O-(4-triphenylphosphoniumbutyl) quercetin iodide (QTM-7BTPI)-or Quercetin itself induced no or little superoxide production and cell death. Q-7BTPI did not cause a significant perturbation of the mitochondrial transmembrane potential or of respiration in cells. On the other hand its presence led to inhibition of glutathione peroxidase, an effect expected to accentuate oxidative stress by interfering with the elimination of H(2)O(2). An exogenous permeable glutathione precursor determined a strong increase of cellular glutathione levels but did not rescue the cells. Death induction was selective for fast-growing C-26 tumoral cells and mouse embryonic fibroblasts (MEFs) while sparing slow-growing MEFs. This suggests a possible use of Q-7BTPI as a chemotherapeutic agent.

Acetal derivatives as prodrugs of resveratrol.

The pharmacological exploitation of resveratrol is hindered by rapid phase-II conjugative metabolism in enterocytes and hepatocytes. One approach to the solution of this problem relies on prodrugs. We report the synthesis and characterization as well as the assessment of in vivo absorption and metabolism of a set of prodrugs of resveratrol in which the OH groups are engaged in the formal (-OCH2OR) or the more labile acetal (-OCH(CH3)OR) linkages. As carrier group (R) of the prodrug, we have used short ethyleneglycol oligomers (OEG) capped by a terminal methoxy group: -O-(CH2CH2O)n-CH3 (n = 0, 1, 2, 3, 4, 6). These moieties are expected to exhibit, to a degree, the favorable properties of longer polyethyleneglycol (PEG) chains, while their relatively small size makes for a more favorable drug loading capacity. After administration of formal-based prodrugs to rats by oral gavage, significant concentrations of derivatives were measured in blood samples over several hours, in all cases except for n = 0. Absorption was maximal for n = 4. Complete deprotection to give resveratrol and its metabolites was however too slow to be of practical use. Administration of the acetal prodrug carrying tetrameric OEG chains resulted instead in the protracted presence of resveratrol metabolites in blood, consistent with a progressive regeneration of the parent molecule from the prodrug after its absorption. The results suggest that prodrugs of polyphenols based on the acetal bond and short ethyleneglycol oligomers of homogeneous size may be a convenient tool for the systemic delivery of the unconjugated parent compound.