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Oral delivery of biopharmaceuticals, as insulin, is hampered by rapid degradation and inefficient absorption in the gastrointestinal tract (GIT). To solve this, a new class of biodegradable poly(lactic-co-glycolic)-poly(ethylene glycol) (PLGA-PEG) mucodiffusive nanoparticles (NPs) was designed. Specifically, these were decorated with site-specific conjugated human albumin, engineered for improved pH dependent binding to the neonatal Fc receptor (FcRn), which naturally mediates transport of albumin across the intestinal epithelium. The designed NPs of monodisperse 150 nm in size were 10% loaded with insulin and their surface was successfully functionalized with human albumin. Importantly, the engineered albumin-functionalized NPs bound human FcRn favorably in a pH dependent manner and showed enhanced transport across polarized cell layers. When orally administered to human FcRn expressing mice induced with diabetes, a reduction of glycemia was measured as a function of receptor targeting, with up to around 40% reduction after 1 h post-delivery. Thus, biodegradable PLGA-PEG NPs decorated with human albumin for improved FcRn-dependent transport offer a novel attractive strategy for delivery of encapsulated biopharmaceuticals across intestinal barriers.

Prevalence of chronic inflammation of the gastrointestinal tract is increasing, emerging as a public health challenge. Conventional drug delivery systems targeting the colon have improved the treatment of inflammatory bowel disease. However, therapy frequently results in inconsistent efficacy and toxicity problems. Novel approaches based on nanoparticles offer several advantages over conventional dosage forms due to their ability to selectively target inflamed tissues. Several formulation efforts have been made in order to obtain increasingly selective nanosized systems, some with promising results in animal models of colitis. Despite all advances, no nanomedicines are yet approved for clinical use in inflammatory bowel disease. This review discusses the most recent efforts made toward the development of nanoparticles for regulating chronic intestinal inflammation.

The human immunodeficiency virus (HIV) uses the brain as reservoir, which turns it as a promising target to fight this pathology. Nanoparticles (NPs) of poly(lactic-co-glycolic) acid (PLGA) are potential carriers of anti-HIV drugs to the brain, since most of these antiretrovirals, as efavirenz (EFV), cannot surpass the blood–brain barrier (BBB). Forasmuch as the conventional production methods lack precise control over the final properties of particles, microfluidics emerged as a prospective alternative. This study aimed at developing EFV-loaded PLGA NPs through a conventional and microfluidic method, targeted to the BBB, in order to treat HIV neuropathology. Compared to the conventional method, NPs produced through microfluidics presented reduced size (73 nm versus 133 nm), comparable polydispersity (around 0.090), less negative zeta-potential (−14.1 mV versus −28.0 mV), higher EFV association efficiency (80.7% versus 32.7%) and higher drug loading (10.8% versus 3.2%). The microfluidics-produced NPs also demonstrated a sustained in vitro EFV release (50% released within the first 24 h). NPs functionalization with a transferrin receptor-binding peptide, envisaging BBB targeting, proved to be effective concerning nuclear magnetic resonance analysis (δ = −0.008 ppm; δ = −0.017 ppm). NPs demonstrated to be safe to BBB endothelial and neuron cells (metabolic activity above 70%), as well as non-hemolytic (1–2% of hemolysis, no morphological alterations on erythrocytes). Finally, functionalized nanosystems were able to interact more efficiently with BBB cells, and permeability of EFV associated with NPs through a BBB in vitro model was around 1.3-fold higher than the free drug.

The clinical translation of the multiple pharmacological effects of resveratrol (RSV) found in preclinical studies has been impaired by its poor bioavailability, due to poor solubility and rapid metabolism and elimination. The inclusion of this molecule in medicines or functional food products will be ineffective unless suitable systems are developed. Zein protein may constitute an inexpensive, safe, and effective choice to produce nanoparticles (NPs) to incorporate hydrophobic molecules and overcome the bioavailability issues of RSV. In this work, we loaded RSV into zein NPs by using a nanoprecipitation method. Unloaded and RSV-loaded NPs presented average diameter values in the range of 120-180 nm, narrow size distribution (polydispersity index 0.150), and zeta potential of around + 20 mV. The association efficiency of the drug was equal to or greater than 77% for different initial drug loads. Scanning electron microscopy imaging revealed that zein NPs were round-shaped and presented a smooth surface. Aqueous suspensions of zein NPs were stable for at least 1 month when stored at 4 °C. The freeze-drying of zein NPs using sucrose as cryoprotectant allowed an easy re-suspension of NPs in water without significantly changing the initial colloidal properties. RSV-loaded NPs presented low cytotoxicity to the human colorectal Caco-2 and HT29-MTX cell lines. Finally, permeability studies of RSV across Caco-2 and Caco-2/HT29-MTX evidenced some ability of zein NPs to protect RSV from metabolism events. However, further investigation is needed in order to confirm the possible role of zein NPs in the metabolic stability of RSV. Overall, zein NPs may present the potential to circumvent bioavailability issues of RSV. Graphical abstract.

The rectal administration of drugs has been an enduring medical practice for either the management of local or systemic conditions. Although mostly regarded as an alternative to other delivery routes, the colorectal mucosa offers an effective pathway for enhanced systemic bioavailability of many active molecules. The fairly stable physicochemical and enzymatic environment of the mucosa and the possibility of partially avoiding the hepatic first-pass effect are some of the potential advantages of rectal drug delivery. At the same time, higher drug levels of drugs can be achieved at colorectal fluids and tissues, which can aid management of local conditions. However, problems with patient acceptability as well as poor and erratic drug absorption may impair efficient use of the rectal drug delivery route. The valuable features of nanotechnology-based systems for mucosal use are well recognized, and their potential as carriers for drug delivery has already been proven for different medical applications/delivery routes. Although still limited, the development of rectal nanomedicines with therapeutic, diagnostic, and prophylactic purposes is steadily emerging and may circumvent some of the problems associated with the more standard delivery approaches. This review discusses the rationale behind the use of nanotechnology-based strategies for rectal drug delivery and provides a critical overview on the various types of nanosystems proposed so far.

Dense surface modification with short chain polyethylene glycol (PEG) has been previously demonstrated as favoring the transport of nanoparticles (NPs) across mucus. However, the ability of such approach to influence the distribution and retention of NPs along the length of the colorectum after rectal delivery has not been previously established. Herein, the distribution and retention of poly(lactic- co -glycolic acid) NPs modified with PEG in a non-covalent fashion are reckoned in a mouse model. Despite overall rapid depletion, both PEG-modified and non-modified NPs are able to reach the middle segment of the colon. PEG-modified NPs are able to enhance retention up to at least two hours post-administration, contrasting with nearly residual levels observed for non-modified NPs after 15 min. The ability of PEG-modified NPs to putatively cross mucus also appears to promote association with tissues. Overall, the work provides significant insights as to the behavior of NPs in the colorectum, which could be valuable for the development of rectal nanomedicines. It further reinforces the potential usefulness of PEG-modified NPs as mucus-penetrating carriers for mucosal drug delivery.

Type 2 diabetes makes up approximately 85% of all diabetic cases and it is linked to approximately one-third of all hospitalisations. Newer therapies with long-acting biologics such as glucagon-like peptide-1 (GLP-1) analogues have been promising in managing the disease, but they cannot reverse the pathology of the disease. Additionally, their parenteral administration is often associated with high healthcare costs, risk of infections, and poor patient adherence associated with phobia of needles. Oral delivery of these compounds would significantly improve patient compliance, however, poor enzymatic stability and low permeability across the gastrointestinal tract makes this task challenging. In the present work, large pore dendritic silica nanoparticles (DSNPs) with a pore size of ~10 nm were prepared, functionalized, and optimized in order to achieve high peptide loading and improve intestinal permeation of exenatide, a GLP-1 analogue. Compared to the loading capacity of the most popular, Mobil Composition of Matter No. 41 (MCM-41) with small pores, DSNPs showed significantly high loading owing to their large and dendritic pore structure. Among the tested DSNPs, pristine and phosphonate-modified DSNPs (PDSNPs) displayed remarkable loading of 40 and 35% w/w, respectively. Furthermore, particles successfully coated with positively charged chitosan reduced the burst release of exenatide at both pH 1.2 and 6.8. Compared with free exenatide, both chitosan-coated and uncoated PDSNPs enhanced exenatide transport through the Caco-2 monolayer by 1.7 fold. Interestingly, when a triple co-culture model of intestinal permeation was used, chitosan-coated PDSNPs performed better compared to both PDSNPs and free exenatide, which corroborated our hypothesis behind using chitosan to interact with mucus and improve permeation. These results indicate the emerging role of large pore silica nanoparticles as promising platforms for oral delivery of biologics such as exenatide.

Nanotechnology-based systems have been proposed for rectal drug delivery, often rendering promising outcomes concerning disease prophylaxis or therapeutics. However, nanocarriers often feature reduced colorectal retention when administered in liquid vehicles (enemas). Semi-solid platforms may be considered as alternative but usually result in limited local distribution. Thermosensitive enemas undergoing sol-gel transition just below body temperature have been used for abbreviating these issues, but the actual impact on the colorectal distribution and retention of incorporated nanosystems is not clear. We prepared and characterized a potential drug delivery platform by incorporating poly(lactic-co-glycolic acid)-based nanoparticles (170-180 nm mean hydrodynamic diameter) into a poloxamer 407-based thermosensitive enema (NPs-in-thermo). The system featured suitable functional properties for rectal administration such as sol-gel transition temperature of approximately 27-28 °C, sol-gel transition time of 1.6 min, and viscosity around 31 and 2100 mPa s at 20 °C and 37 °C, respectively. NPs-in-thermo presented osmolality and pH values deemed compatible with the colorectal compartment, as well as reduced toxicity to the Caco-2 colorectal cell line. The composite system was also used to incorporate the anti-HIV microbicide model drug dapivirine. In vitro studies showed that dapivirine-loaded NPs-in-thermo was able to provide overall faster drug release as compared to dapivirine directly dispersed into phosphate buffered saline or the thermosensitive enema base. Finally, NPs-in-thermo was tested for distribution and retention in a mouse model by in vivo and ex vivo near infrared imaging. Qualitative and semi-quantitative data indicated that NPs exhibited slower but overall wider distribution and enhanced retention in the distal colon of mice treated intrarectally with NPs-in-thermo, namely when compared to NPs dispersed in liquid phosphate buffered saline. Overall, our data support that thermosensitive enemas may provide suitable platforms for the rectal administration of polymeric NPs, namely in the context of drug delivery.

Combining two or more antiretroviral drugs in one medical product is an interesting but challenging strategy for developing topical anti-HIV microbicides. We developed a new vaginal delivery system comprising the incorporation of nanoparticles (NPs) into a polymeric film base - NPs-in-film - and tested its ability to deliver tenofovir (TFV) and efavirenz (EFV). EFV-loaded poly(lactic-co-glycolic acid) NPs were incorporated alongside free TFV into fast dissolving films during film manufacturing. The delivery system was characterized for physicochemical properties, as well as genital distribution, local and systemic 24h pharmacokinetics (PK), and safety upon intravaginal administration to mice. NPs-in-film presented suitable technological, mechanical and cytotoxicity features for vaginal use. Retention of NPs in vivo was enhanced both in vaginal lavages and tissue when associated to film. PK data evidenced that vaginal drug levels rapidly decreased after administration but NPs-in-film were still able to enhance drug concentrations of EFV. Obtained values for area-under-the-curve for EFV were around one log10 higher than those for the free drugs in aqueous vehicle (phosphate buffered saline). Film alone also contributed to higher and more prolonged local drug levels as compared to the administration of TFV and EFV in aqueous vehicle. Systemic exposure to both drugs was low. NPs-in-film was found to be safe upon once daily vaginal administration to mice, with no significant genital histological changes or major alterations in cytokine/chemokine profiles being observed. Overall, the proposed NPs-in-film system seems to be an interesting delivery platform for developing combination vaginal anti-HIV microbicides.

Topical pre-exposure prophylaxis (PrEP) with antiretroviral drugs holds promise in preventing vaginal transmission of HIV. However, significant biomedical and social issues found in multiple past clinical trials still need to be addressed in order to optimize protection and users’ adherence. One approach may be the development of improved microbicide products. A novel delivery platform comprising drug-loaded nanoparticles (NPs) incorporated into a thin polymeric film base (NPs-in-film) was developed in order to allow the vaginal administration of the microbicide drug candidate tenofovir. The system was optimized for relevant physicochemical features and characterized for biological properties, namely cytotoxicity and safety in a mouse model. Tenofovir-loaded poly(lactic-co-glycolic acid) (PLGA)/stearylamine (SA) composite NPs with mean diameter of 127 nm were obtained with drug association efficiency above 50%, and further incorporated into an approximately 115 μm thick, hydroxypropyl methylcellulose/poly(vinyl alcohol)-based film. The system was shown to possess suitable mechanical properties for vaginal administration and to quickly disintegrate in approximately 9 min upon contact with a simulated vaginal fluid (SVF). The original osmolarity and pH of SVF was not affected by the film. Tenofovir was also released in a biphasic fashion (around 30% of the drug in 15 min, followed by sustained release up to 24 h). The incorporation of NPs further improved the adhesive potential of the film to ex vivo pig vaginal mucosa. Cytotoxicity of NPs and film was significantly increased by the incorporation of SA, but remained at levels considered tolerable for vaginal delivery of tenofovir. Moreover, histological analysis of genital tissues and cytokine/chemokine levels in vaginal lavages upon 14 days of daily vaginal administration to mice confirmed that tenofovir-loaded NPs-in-film was safe and did not induce any apparent histological changes or pro-inflammatory response. Overall, obtained data support that the proposed delivery system combining the use of polymeric NPs and a film base may constitute an exciting alternative for the vaginal administration of microbicide drugs in the context of topical PrEP. Statement of Significance The development of nanotechnology-based microbicides is a recent but promising research field seeking for new strategies to circumvent HIV sexual transmission. Different reports detail on the multiple potential advantages of using drug nanocarriers for such purpose. However, one important issue being frequently neglected regards the development of vehicles for the administration of microbicide nanosystems. In this study, we propose and detail on the development of a nanoparticle-in-film system for the vaginal delivery of the microbicide drug candidate tenofovir. This is an innovative approach that, to our best knowledge, had never been tested for tenofovir. Results, including those from in vivo testing, sustain that the proposed system is safe and holds potential for further development as a vaginal microbicide product.

Prevention plays an invaluable role in the fight against HIV/AIDS. The use of microbicides is considered an interesting potential approach for topical pre-exposure prophylaxis of HIV sexual transmission. The prospects of having an effective product available are expected to be fulfilled in the near future as driven by recent and forthcoming results of clinical trials. Different dosage forms and delivery strategies have been proposed and tested for multiple microbicide drug candidates presently at different stages of the development pipeline. One particularly interesting approach comprises the application of nanomedicine principles to the development of novel anti-HIV microbicides, but its implications to efficacy and safety are not yet fully understood. Nanotechnology-based systems, either presenting inherent anti-HIV activity or acting as drug nanocarriers, may significantly influence features such as drug solubility, stability of active payloads, drug release, interactions between active moieties and virus/cells, intracellular drug delivery, drug targeting, safety, antiviral activity, mucoadhesive behavior, drug distribution and tissue penetration, and pharmacokinetics. The present manuscript provides a comprehensive and holistic overview of these topics as relevant to the development of vaginal and rectal microbicides. In particular, recent advances pertaining inherently active microbicide nanosystems and microbicide drug nanocarriers are discussed.

Despite research efforts to discover new drugs for Parkinson treatment, the majority of candidates fail in preclinical and clinical trials due to inadequate pharmacokinetic properties, namely blood-brain barrier permeability. Within the high demand to introduce new drugs to market, nanotechnology can be used as a solution. Accordingly, PEGylated PLGA nanoparticles (NPs) were used as a smart delivery carrier to solve the suboptimal aqueous solubility, which precludes its use in in vivo assays, of a potent, reversible, and selective monoamine oxidase B inhibitor (IMAO-B) (coumarin C75, IC50 = 28.89 ± 1.18 nM). Long-term stable PLGA@C75 NPs were obtained by nanoprecipitation method, with sizes around 105 nm and a zeta potential of -10.1 mV. The encapsulation efficacy was around 50%, achieving the final C75 concentration of 807 ± 30 μM in the nanoformulation, which corresponds to a therapeutic concentration 27828-fold higher than its IC50 value. Coumarin C75 showed cytotoxic effects at 50 μM after 48 and 72 h of exposure in SH-SY5Y, Caco-2, and hCMEC/D3 cell lines. Remarkably, no cytotoxic effects were observed after nanoencapsulation. Furthermore, the data obtained from the P-gp-Glo assay and the cellular uptake studies showed that C75 is a P-glycoprotein (P-gp) substrate having a lower uptake profile in intestinal and brain endothelial cells. Moreover, it was shown that this membrane transporter influences C75 permeability profile in Caco-2 and hCMEC/D3 cells. Interestingly, PLGA NPs inhibited P-gp and were able to cross intestinal and brain membranes allowing the successful transport of C75 through this type of biological barriers. Overall, this work showed that nanotechnology can be used to solve drug discovery related drawbacks.

Antiretroviral drug nanocarriers hold great promise for developing anti-human immunodeficiency virus (HIV) rectal microbicides. However, challenges remain, namely, concerning which properties are more suited for enhancing colorectal distribution and retention of microbicide compounds. In this work, we developed and assessed the in vitro and in vivo performance of poly(lactic- co-glycolic acid) (PLGA)-based nanoparticles (NPs) as carriers for the model drug efavirenz (EFV). We particularly focused on the effect of noncovalent poly(ethylene glycol) coating of PLGA NPs (PEG-PLGA NPs) conferring a mucus-diffusive behavior on the pharmacokinetics (PK) of EFV following rectal administration to mice. Drug-loaded PLGA NPs and PEG-PLGA NPs (200-225 nm) were obtained by nanoprecipitation. Both types of systems were able to retain native antiretroviral activity of EFV in vitro, while featuring lower cytotoxicity against different epithelial cell lines and HIV target cells. Also, PLGA NPs and PEG-PLGA NPs were readily taken up by colorectal cell lines and mildly reduced EFV permeation while increasing membrane retention in Caco-2 and Caco-2/HT29-MTX cell monolayer models. When administered intrarectally to CD-1 mice in phosphate-buffered saline (pH 7.4), EFV-loaded PEG-PLGA NPs consistently provided higher drug levels in colorectal tissues and lavages, as compared to free EFV or drug-loaded PLGA NPs. Mean values for the area-under-the-curve between 15 min and 12 h following administration were particularly higher for PEG-PLGA NPs in distal and middle colorectal tissues, with relative bioavailability values of 3.7 and 29, respectively, as compared to free EFV (2.2 and 6.0 over PLGA NPs, respectively). Systemic exposure to EFV was reduced for all treatments. NPs were further shown safe after once-daily administration for 14 days, as assessed by histological analysis of colorectal tissues and chemokine/cytokine assay of rectal lavages. Overall, PEG-PLGA NPs demonstrated to be safe carriers for rectal microbicide drug delivery and able to provide enhanced local PK that could be valuable in preventing rectal HIV transmission.

Nelfinavir mesylate (NFV), a human immunodeficiency virus (HIV) protease inhibitor, is an integral component of highly active anti retro viral therapy (HAART) for management of AIDS. NFV possesses pH-dependent solubility and has low and variable bioavailability hampering its use in therapeutics. Lipid-based particulates have shown to improve solubility of poorly water soluble drugs and oral absorption, thereby aiding in improved bioavailability. The current study compares potential of vesicular and solid lipid nanocarriers of NFV with drug nanocrystallites and microvesicular systems like cochleates in improving bioavailability of NFV. The paper outlines investigation of systems using in vitro models like in vitro lipolysis, in vitro release, and permeation through cell lines to predict the in vivo potential of nanocarriers. Finally, in vivo pharmacokinetic study is reported which provided proof of concept in sync with results from in vitro studies. Graphical Abstract ᅟ.

Prevention strategies play a key role in the fight against HIV/AIDS. Vaginal and rectal microbicides hold great promise in tackling sexual transmission of HIV-1, but effective and safe products are yet to be approved and made available to those in need. While most efforts have been placed in finding and testing suitable active drug candidates to be used in microbicide development, the last decade also saw considerable advances in the design of adequate carrier systems and formulations that could lead to products presenting enhanced performance in protecting from infection. One strategy demonstrating great potential encompasses the use of nanosystems, either with intrinsic antiviral activity or acting as carriers for promising microbicide drug candidates. Polymeric nanoparticles, in particular, have been shown to be able to enhance mucosal distribution and retention of promising antiretroviral compounds. One important aspect in the development of nanotechnology-based microbicides relates to the design of pharmaceutical vehicles that allow not only convenient vaginal and/or rectal administration, but also preserve or even enhance the performance of nanosystems. In this manuscript, we revise relevant work concerning the selection of vaginal/rectal dosage forms and vehicle formulation development for the administration of microbicide nanosystems. We also pinpoint major gaps in the field and provide pertinent hints for future work. This work was supported by Programa Gilead GÉNESE, Gilead Portugal (refs. PGG/046/2015 and PGG/002/2016). This article is a result of the project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was financed by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020-Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT-Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274), and also Partnership Agreement PT2020 UID/QUI/50006/2013-POCI/01/0145/FEDER/007265. J.G. gratefully acknowledges FCT for financial support (SFRH/BD/140271/2018 scholarship).

The oral route is the most preferable one when it comes to drug administration. Different animal models have been used to characterize the fate of potential medicines upon oral delivery but fail to clarify specific events occurring at localized sites of the gastrointestinal tract, particularly at the small intestine. We developed a new mouse intra-intestinal infusion model that enabled the direct administration of substances (such as drugs or nanoparticle drug carriers) in the small intestine through an implanted catheter, which can be maintained for prolonged periods of time. The location of catheter insertion can be previously determined as more proximal or distal, allowing to test specific portions of the intestine. Since the model is able to presumably maintain normal physiological characteristics, namely the mucus coating of the intestinal wall, it allowed studying the distribution of different nanoparticles upon localized intra-intestinal administration. The hereby proposed mouse model has the potential to be useful in other types of studies, namely in clarifying localized processes occurring at specific sites of the intestine.

Aim: Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. Materials & methods: Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. Results: Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. Conclusion: Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration.

Women are particularly vulnerable to sexual HIV-1 transmission. Oral pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) is highly effective in avoiding new infections in men, but protection has only been shown to be moderate in women. Such differences have been associated, at least partially, to poor drug penetration of the lower female genital tract and the need for strict adherence to continuous daily oral intake of TDF/FTC. On-demand topical microbicide products could help circumvent these limitations. We developed electrospun fibers based on polycaprolactone (PCL fibers) or liposomes associated to poly(vinyl alcohol) (liposomes-in-PVA fibers) for the vaginal co-delivery of TDF and FTC, and assessed their pharmacokinetics in mice. PCL fibers and liposomes-in-PVA fibers were tested for morphological and physico chemical properties using scanning electron microscopy, differential scanning calorimetry and X-ray diffrac tometry. Fibers featured organoleptic and mechanical properties compatible with their suitable handling and vaginal administration. Fluorescent quenching of mucin in vitro – used as a proxy for mucoadhesion – was intense for PCL fibers, but mild for liposomes-in-PVA fibers. Both fibers were shown safe in vitro and able to rapidly release drug content (15–30 min) under sink conditions. Liposomes-in-PVA fibers allowed increasing genital drug concentrations after a single intravaginal administration when compared to continuous daily treatment for five days with 25-times higher oral doses. For instance, the levels of tenofovir and FTC in vaginal lavage were around 4- and 29-fold higher, respectively. PCL fibers were also superior to oral treatment, although to a minor extent (approximately 2-fold higher drug concentrations in lavage). Vaginal tissue drug levels were generally low for all treatments, while systemic drug exposure was negligible in the case of fibers. These data suggest that proposed fibers may provide an interesting alternative or an ancillary option to oral PrEP in women., This work was financed by Programa Gilead GÉNESE (refs. PGG/ 046/2015) and Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Ensino Superior in the framework of the project “Institute for Research and Innovation in Health Sciences” UID/BIM/04293/2019. The work was also financed by FCT in the framework of the Strategic Funding UID/FIS/04650/2019 and in the ambit of the project POCI-01-0145-FEDER-032651 and PTDC/NAN-MAT/326512017, co-financed by the FEDER, through COMPETE 2020, under PORTUGAL 2020, and FCT. Marlene Lúcio thanks FCT and ERDF for doctoral position Ref. CTTI-150/18-CF(1) in the ambit of the project CONCERT (POCI-01-0145-FEDER-032651 and PTDC/NAN-MAT/326512017).