Oral targeted drug delivery to post-gastrointestinal sites.

As an essential branch of targeted drug delivery, oral targeted delivery is attracting growing attention in recent years. In addition to site-specific delivery for the treatment of locoregional diseases in the gastrointestinal tract (GIT), oral targeted delivery to remote sites beyond the GIT emerges as a cutting-edge research topic. This review aims to provide an overview of the fundamental concepts and most recent advances in this field. Owing to the physiological barriers existing in the GIT, carrier systems should be transported across the enteric epithelia to target remote sites. Recently, pioneer investigations have validated the transport of intact micro- or nanocarriers across gastrointestinal barriers and subsequently to various distal organs and tissues. The microfold (M) cell pathway is the leading mechanism underlying the oral absorption of particulates, but the contribution of the transcellular and paracellular pathways should not be neglected either. In addition to well-acknowledged physicochemical and biological factors, the formation of a protein corona may also influence the biological fate of carrier systems. Although in an early stage of conceptualization, oral targeted delivery to remote diseases has demonstrated promising potential for the treatment of inflammation, tumors, and diseases inflicting the lymphatic and mononuclear phagocytosis systems.

Distribution Characteristics of Microplastics in Surface Seawater off the Yangtze River Estuary Section and Analysis of Ecological Risk Assessment.

Microplastics are widespread in the oceans as a new type of pollutant. Due to the special geographical environment characteristics, the Yangtze River estuary region become hotspot for microplastics research. In 2017 and 2019, surface seawater microplastics samples were collected from five stations off the Yangtze River estuary during four seasons (spring, summer, autumn, and winter). The abundance and characteristics of microplastics in seawater were researched. The results showed that microplastics widely existed in surface seawater; the average abundance of microplastics in seawater was (0.17 ± 0.14) items/m3 (0.00561 ± 0.00462) mg/m3; and accounting for 80% of the total plastic debris, the abundance of microplastics was at moderately low levels compared to national and international studies. The particle size of most microplastics was between 1 mm to 2 mm, accounting for 36.1% of the total microplastics. The main shapes of microplastics were fiber, flake, and line, accounting for 39.5%, 28.4%, and 20.8%, respectively. Polypropylene, polyethylene terephthalate, and polyethylene were the main components of microplastics, accounting for 41.0%, 25.1%, and 24.9%, respectively. Yellow, green, black, and transparent were the most common colors, accounting for 21.9%, 19.6%, 16.5%, and 15.7%, respectively. This study shows that the spatial distribution of microplastics in the surface waters off the Yangtze River estuary shows a decreasing trend from nearshore to farshore due to the influence of land-based inputs, hydrodynamics, and human activities; the distribution of microplastics has obvious seasonal changes, and the level of microplastic pollution is higher in summer. The potential ecological risk of microplastics in the surface waters off the Yangtze River estuary is relatively small.

Special Issue "Delivery Systems of Peptides and Proteins: Challenges, Status Quo and Future Perspectives".

Peptides and proteins have emerged as more important therapeutic molecules compared to small molecular chemicals due to their high specificity and efficacy and low toxicity [...].

Establishment of In Vitro Dissolution Based on Similarity with In Vivo Dissolution: A Case Study on Aripiprazole.

In vitro dissolution that predicts the in vivo performance of solid preparations is extremely important in formulation optimization. Fraction absorbed (Fa) has been used to screen in vitro dissolution protocols based on the idea of in vitro-in vivo correlation (IVIVC) but failed to increase the success rate due to the inaccuracy of the Fa. The essence of IVIVC is the correlation between in vitro dissolution and in vivo dissolution. We tried to establish in vitro dissolution protocol via similarity with in vivo dissolution using aripiprazole (APZ) as a model drug. Hybrid APZ crystals (APZ-HCs) were prepared by physically embedding aggregation-caused quenching (ACQ) fluorophores inside the lattice to measure the in vivo dissolution. The process did not change the physicochemical properties and crystallinity of APZ. The fluorophore illuminated APZ crystals but was quenched upon dissolution of APZ-HCs in aqueous media, enabling monitoring intact APZ-HCs in real-time. The good correlation between fluorescent quenching and dissolution of APZ-HCs justified reliable quantification of intact APZ crystals. The residual percentage of fluorescence intensity in rats treated by APZ-HCs was recorded with time, which was converted to in vivo dissolution by the difference from 100%. The in vivo dissolution was validated with the Fa. The in vitro dissolution profile of APZ was set up via a similarity factor larger than 50 in comparison with the in vivo dissolution. The study provides a novel idea and method to establish in vitro dissolution protocol.

Translation of ionic liquids to be enteric nanoparticles for facilitating oral absorption of cyclosporine A.

Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2 h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.

"Hook&Loop" multivalent interactions based on disk-shaped nanoparticles strengthen active targeting.

How to enhance active targeting efficiency remains a challenge. Multivalent interactions play a crucial role in improving the binding ability between ligands and receptors. It is hypothesized that nanoparticles bearing a flat conformation attain simultaneous formation of multiple ligand-receptor bindings, which could be vividly metaphorized by the "Hook&Loop" rationale. In this study, spherical, rod-shaped and disk-shaped folic acid-modified red blood cell membrane-coated biomimetic mesoporous silica nanoparticles (FRMSNs) were prepared to verify the shape-based multivalent interactions. The fundamental concepts of multivalent interactions have been proved by a series of both in vitro and in vivo evaluations. Physical characterization confirmed the morphology, shape and surface features of FRMSNs. Strengthened binding and internalization of disk-shaped FRMSNs by K562 cells stresses the merits of multivalent interactions. Whereas Bio-TEM visually demonstrates the proposed "plane" contact of disk-shaped particles with cells, quantification further confirmed strengthened "plane" binding affinity with folate binding proteins owing to multivalent interactions. In K562 xenograft mice, doxorubicin-loaded disk-shaped FRMSNs effectively slowed down chronic myeloid leukemia progression. It is concluded that disks favor multivalent interactions which leads to enhanced active targeting efficiency.

Novel Pharmaceutical Strategies for Enhancing Skin Penetration of Biomacromolecules.

Skin delivery of biomacromolecules holds great advantages in the systemic and local treatment of multiple diseases. However, the densely packed stratum corneum and the tight junctions between keratinocytes stand as formidable skin barriers against the penetration of most drug molecules. The large molecular weight, high hydrophilicity, and lability nature of biomacromolecules pose further challenges to their skin penetration. Recently, novel penetration enhancers, nano vesicles, and microneedles have emerged as efficient strategies to deliver biomacromolecules deep into the skin to exert their therapeutic action. This paper reviews the potential application and mechanisms of novel skin delivery strategies with emphasis on the pharmaceutical formulations.

The in vivo fate of polymeric micelles.

This review aims to provide a systemic analysis of the in vivo, as well as subcellular, fate of polymeric micelles (PMs), starting from the entry of PMs into the body. Few PMs are able to cross the biological barriers intact and reach the circulation. In the blood, PMs demonstrate fairly good stability mainly owing to formation of protein corona despite controversial results reported by different groups. Although the exterior hydrophilic shells render PMs "long-circulating", the biodistribution of PMs into the mononuclear phagocyte systems (MPS) is dominant as compared with non-MPS organs and tissues. Evidence emerges to support that the copolymer poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) is first broken down into pieces of PEG and PLA and then remnants to be eliminated from the body finally. At the cellular level, PMs tend to be internalized via endocytosis due to their particulate nature and disassembled and degraded within the cell. Recent findings on the effect of particle size, surface characteristics and shape are also reviewed. It is envisaged that unraveling the in vivo and subcellular fate sheds light on the performing mechanisms and gears up the clinical translation of PMs.

The long-circulating effect of pegylated nanoparticles revisited via simultaneous monitoring of both the drug payloads and nanocarriers.

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

ROS/RNS and Base Dual Activatable Merocyanine-Based NIR-II Fluorescent Molecular Probe for in vivo Biosensing.

Inflammation usually results in high-level reactive oxygen species (ROS) and reactive nitrogen species (RNS) not only in acidic tissue but also in alkaline tissue. However, noninvasively in vivo monitoring reactive species specifically within alkaline tissue remains a huge challenge. Here we introduce a dual activatable fluorescent probe PN910 located in the second near-infrared window (NIR-II, 900-1700 nm), which shows high selectivity toward H2 O2 and OONO- at pH beyond 7.4. Then we verified that PN910 could be used for the real-time, specific and accurate monitoring of cystitis and colitis for living animals. This report presents a unique approach to the development of dual activatable probe for in vivo biosensing.

A 168-year temperature recording based on tree rings and latitude differences in temperature changes in northeast China.

A ring-width series was developed from Dahurian larch (Larix gmelinii) in the northeastern forest area of Inner Mongolia, China. By analyzing the relationships between tree-ring data and climate records, an August-September mean maximum temperature (T89) series during 1845 and 2012 was reconstructed based on a simple linear regression equation. This reconstructed series explained 40.9% variance of the observed temperature from 1959 to 2012. The reconstructed T89 series was consistent with the historical disaster events caused by extreme climate (e.g., flood, frost disaster, and cold damage). Besides, the temperature comparisons showed that the year in which the warm months (April-September) in northeast China began to warm up has latitude differences. It started with a gradual delay from north to south, starting 1980 in the south region, after 1950 AD in the central region and after 1940 in the north region. Our study can enrich high-resolution temperature series in Northeast China and help clarify the characteristic of recent warming in northeast China.

In vivo dissolution of poorly water-soluble drugs: Proof of concept based on fluorescence bioimaging.

In vitro‒in vivo correlation (IVIVC) of solid dosage forms should be established basically between in vitro and in vivo dissolution of active pharmaceutical ingredients. Nevertheless, in vivo dissolution profiles have never been accurately portrayed. The current practice of IVIVC has to resort to in vivo absorption fractions (F a). In this proof-of-concept study, in vivo dissolution of a model poorly water-soluble drug fenofibrate (FNB) was investigated by fluorescence bioimaging. FNB crystals were first labeled by near-infrared fluorophores with aggregation-caused quenching properties. The dyes illuminated FNB crystals but quenched immediately and absolutely once been released into aqueous media, enabling accurate monitoring of residual drug crystals. The linearity established between fluorescence and crystal concentration justified reliable quantification of FNB crystals. In vitro dissolution was first measured following pharmacopoeia monograph protocols with well-documented IVIVC. The synchronicity between fluorescence and in vitro dissolution of FNB supported using fluorescence as a measure for determination of dissolution. In vitro dissolution correlated well with in vivo dissolution, acquired by either live or ex vivo imaging. The newly established IVIVC was further validated by correlating both in vitro and in vivo dissolution with F a obtained from pharmacokinetic data.

Simulation of the In Vivo Fate of Polymeric Nanoparticles Traced by Environment-Responsive Near-Infrared Dye: A Physiologically Based Pharmacokinetic Modelling Approach.

The application of physiologically based pharmacokinetic models to nanoparticles is still very restricted and challenging, owing to the complicated in vivo transport mechanisms involving nanoparticles, including phagocytosis, enhanced permeability and retention effects, cellular recognition, and internalisation, enzymatic degradation, lymphatic transport, and changes in physical properties. In our study, five nanoparticle formulations were synthesised using polycaprolactone as a framework material and methoxy poly (ethylene glycol)-poly(ε-caprolactone) as a long-circulating decorating material, as well as types of environmentally responsive near-infrared aza-boron-dipyrromethene dyes. According to quantification data and direct visualisation involving specific organs, a phagocytosis physiologically based pharmacokinetic model was developed to describe the dynamics of nanoparticles within and between organs in mice, considering cellular mechanisms involving phagocytosis and enhanced permeability and retention effects. Our results offer a better understanding of the in vivo fate of polymeric nanoparticles.

Bright and Stable NIR-II J-Aggregated AIE Dibodipy-Based Fluorescent Probe for Dynamic In†Vivo Bioimaging.

Organic dyes emitting in the second near-infrared (NIR-II, 900-1700 nm) window, with high molar extinction coefficients (MEC) and quantum yields (QY) in aqueous, are essential for in vivo bioimaging and biosensing. In this work, we developed a dibodipy-based aggregation-induced emission (AIE) fluorescent probe, THPP, to meet this aim. THPP exhibits a high MEC and has intensified absorption and emission in J-aggregated state, which significantly enhance the fluorescence intensity (≈55 folds) and extend the maximal absorption/emission wavelengths to 970/1010 nm in NIR-II region. Based on the bright THPP, imaging with a high frame rate (34 frames per second) at a deep "valid penetration depth" up to 6 mm can be achieved. This enabled simultaneous and dynamic imaging of vasculatures and deep tissues. Besides, we succeeded in monitoring the respiratory rate of acute-lung-injury mice and tracing the collateral circulation process with a high frame rate.

The biological fate of orally administered mPEG-PDLLA polymeric micelles.

The biological fate of polymeric micelles (PMs) following oral administration was investigated in this study to better understand the contribution of transport of integral PMs to oral absorption. To track integral PMs, near-infrared fluorophores with aggregation-caused quenching properties were utilized to label PMs comprised of methoxy poly(ethylene glycol)-poly(D,L-lactic acid) (mPEG-PDLLA) copolymers and methoxy poly(ethylene glycol)-distearoyl phosphoethanolamine (DSPE-PEG). The particle size of PMs prepared from mPEG2.5k-PDLLA1.25k, mPEG2.5k-PDLLA2.5k, mPEG5k-PDLLA3k, mPEG5k-PDLLA5k and DSPE-PEG2k was 24.5, 29.5, 34.0, 41.4 and 15.6 nm, respectively. After oral administration by gavage to rats, PMs were retained in the gastrointestinal tract for at least 4 h, and the copolymer block chain lengths did not have significant influence. The emergence of fluorescence in the blood and liver served as direct evidence to support oral absorption of integral PMs. Approximately 1-2% of intact particles were absorbed via the lymphatic pathway, but the total amount of PMs that reach the systemic circulation await further elucidation. Confocal laser scanning microscopy added more evidence to support the penetration of integral PMs into the basolateral tissues of microvilli. Cellular uptake efficiency was about 4-7% in Caco-2 cell lines for all PM groups, but was reduced to 1-3% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 6-12% of integral PMs were transported across Caco-2/HT29-MTX/Raji monolayers, whereas only approximately one-tenth of that amount was transported across Caco-2 and Caco-2/HT29-MTX monolayers. Differences, but not statistically significant, were observed between PM groups in lymphatic uptake, biodistribution, cellular uptake and trans-monolayer transport, possibly owing to difference in block chain lengths as well as particle size. In conclusion, evidence obtained in this study supports penetration of integral PMs across the enteric epithelia, but the total amount may be limited.

Insight into the in vivo translocation of oral liposomes by fluorescence resonance energy transfer effect.

Liposomes have been broadly used in pharmaceutical field to overcome oral absorption barriers, such as gastric acid, tenacious mucus or intestinal epithelia. However, the concrete in vivo absorption mechanisms of liposomes are still indistinct. This study aims to visually elucidate the effect of particle size and surface characteristics on in vivo translocation of oral liposomes by fluorescence resonance energy transfer (FRET) effect. We fabricated liposomes of various sizes (100 nm, 200 nm and 500 nm) and surface characteristics (anionic, cationic and PEGylated) which are also labeled with FRET probes for discriminating the intact liposomes. We then investigated the in vivo fate of those different liposomes upon oral administration. Results showed that smaller conventional liposomes, cationic and PEGylated liposomes had longer retention time in digestive tract. Few intact liposomes were taken up by intestinal epithelial cells and none were found in circulation. In vivo pharmacokinetics revealed that the smaller, cationic or PEGylated liposomes had higher relative bioavailability. Similar retention time of various liposomes in blood circulation to control solution indicated that liposomes improved oral drug absorption by either prolonging contact time with gastrointestinal tract or increasing penetration ability through mucus barrier, instead of being absorbed integrally into circulation. This study offered new insight into developing highly effective liposomes for oral delivery.

A Tumor-Microenvironment-Responsive Lanthanide-Cyanine FRET Sensor for NIR-II Luminescence-Lifetime In Situ Imaging of Hepatocellular Carcinoma.

Deep tissue imaging in the second near-infrared (NIR-II) window holds great promise for widespread fundamental research. However, inhomogeneous signal attenuation due to tissue absorption and scattering hampers its application for accurate in vivo biosensing. Here, lifetime-based in situ hepatocellular carcinoma (HCC) detection in NIR-II region is presented using a tumor-microenvironment (peroxynitrite, ONOO- )-responsive lanthanide-cyanine Förster resonance energy transfer (FRET) nanosensor. A specially designed ONOO- -responsive NIR-II dye, MY-1057, is synthesized as the FRET acceptor. Robust lifetime sensing is demonstrated to be independent of tissue penetration depth. Tumor lesions are accurately distinguished from normal tissue due to the recovery lifetime. Magnetic resonance imaging and liver dissection results illustrate the reliability of lifetime-based detection in single and multiple HCC models. Moreover, the ONOO- amount can be calculated according to the standard curve.

Effect of particle size on the pharmacokinetics and biodistribution of parenteral nanoemulsions.

This study aims to investigate the effect of particle size on the pharmacokinetics and biodistributions of parenteral blank nanoemulsions (NEs). To monitor intact NEs in vivo, a near-infrared fluorescent dye is utilized to label NEs by exploiting its aggregation-caused quenching (ACQ) properties. After a single intravenous dose of NEs with mean sizes of 70, 200, 500 and 900 nm is administered to rats, the pharmacokinetic profiles are plotted based on semiquantification of the NE particles in blood by monitoring particle-bound fluorescence. All NE groups are cleared from the blood rapidly in a size-dependent manner. Reductions in particle size lead to prolonged residence times in blood which indicates size-dependent effect on the circulation time. Live imaging reveals pervasive distribution of NEs throughout the body in rats with an apparent size-dependency. Ex vivo bioimaging demonstrates the dynamic biodistribution of NEs in different organs and tissues with different patterns. The smallest NEs (70 nm) are prone to be taken up gradually by the liver, whereas the larger NEs are distributed in greater amounts in the spleen and lungs. The distribution in other tissues and organs is quite low. It is concluded that reductions in particle size lead to enhanced circulatory residence and hepatic exposure of NEs.

Slowing down lipolysis significantly enhances the oral absorption of intact solid lipid nanoparticles.

Only a limited amount of orally administered lipid nanoparticles are absorbed as intact particles due to lipolysis by lipases in the gastrointestinal tract. It is hypothesized that by counteracting lipolysis, more particles will survive gastrointestinal digestion and be absorbed as intact particles. In this study, incorporation of a lipase inhibitor orlistat (OLST), as well as polyethylene glycol (PEG) coating, is employed to slow down the lipolysis using solid lipid nanoparticles (SLNs) as model particles. To explore the in vivo behaviors of the particles, near-infrared fluorescent probes with absolute aggregation-caused quenching (ACQ) properties are used to label and track the unmodified, PEG-coated and OLST-loaded SLNs. The in vitro lipolysis study indicates very fast first-order degradation of unmodified SLNs and significantly decreased degradation of OLST-SLNs. Live imaging reveals the same trend of slowed-down lipolysis in vivo which correlates well with the in vitro lipolysis. The scanning of ex vivo gastrointestinal segments confirms the considerably prolonged residence time of OLST-SLNs, mirroring the significantly decreased lipolysis rate. The observation of fluorescence in the blood, though very weak, and in the liver speaks of the oral absorption of intact SLNs. The substantially higher hepatic levels of OLST-SLNs than unmodified SLNs should be attributed to the significantly enhanced survival rate because both particles exhibit similar cellular recognition as well as similar physicochemical properties except for the survival rate. Similarly, slowing down lipolysis also contributes to the significantly enhanced cumulative lymphatic transport of OLST-SLNs (7.56% vs. 1.27% for the unmodified SLNs). The PEG coating slows down the lipolysis rate as well but not to the degree as done by OLST. As a result, the gastrointestinal residence time of PEG-SLNs has been moderately prolonged and the hepatic levels moderately increased. The weakened cellular recognition of PEG-SLNs implies that the enhanced oral absorption is solely ascribed to the slowed-down lipolysis and enhanced mucus penetration. In conclusion, the oral absorption of intact SLNs can be significantly enhanced by slowing down lipolysis, especially by OLST, showing potential as carriers for the oral delivery of labile biomacromolecules.

Adapting liposomes for oral drug delivery.

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.