Microemulsion as a promising carrier for nose to brain delivery: journey since last decade

Shah Brijesh 한국약제학회 2021 Journal of Pharmaceutical Investigation Vol.51 No.6

Background Tight junctions and efflux transporters are two chief bodyguards of the blood–brain barrier that protect the brain and create challenges for the treatment of neurological disorders by hampering the systemic delivery of conventional therapeutics to the brain. Approaches involving drug delivery across the brain are either invasive which require disruption of barrier integrity, leading to develop the risk of neurological changes and brain abscess, or non-invasive patient friendly approach like intranasal delivery. Several investigations have strongly confirmed the direct connection between nose and brain via olfactory and trigeminal pathway which deliver neurotherapeutics directly to the brain bypassing obstructive barriers. Area covered Since last two decades, extensive researches are ongoing for intranasal delivery of drugs in the form of different novel colloidal carriers wherein, microemulsion with their unique composition and small globule size (< 100 nm) have shown higher efficacy in-vivo and revealed their great potential to treat severe brain disorders where rapid onset of action is needed. In this discussion, why intranasal delivery of microemulsion seems to be promising for brain targeting is the foremost focus while, the importance of delivery device for efficient brain targeting is also covered. Expert opinion Considering the translation of positive in-vivo outcomes further into clinical studies and humans, future direction should be aimed at evaluating the suitability of microemulsion with an efficient intranasal delivery device capable of delivering formulation into upper nasal segment. Limitations associated to intranasal delivery of microemulsion such as performing brain distribution studies in most appropriate model resembling humans, impact of diseased condition on the drug absorption and toxicity related to prolonged use, etc. must be addressed in the near future to establish a strong bench to bedside platform.

Biodistribution of Exosomes and Engineering Strategies for Targeted Delivery of Therapeutic Exosomes

Choi Hojun,Choi Yoorim,임화영,Mirzaaghasi Amin,Yoo Jae-Kwang,최철희 한국조직공학과 재생의학회 2021 조직공학과 재생의학 Vol.18 No.4

Exosomes are cell-secreted nano-sized vesicles which deliver diverse biological molecules for intercellular communication. Due to their therapeutic potential, exosomes have been engineered in numerous ways for efficient delivery of active pharmaceutical ingredients to various target organs, tissues, and cells. In vivo administered exosomes are normally delivered to the liver, spleen, kidney, lung, and gastrointestinal tract and show rapid clearance from the blood circulation after systemic injection. The biodistribution and pharmacokinetics (PK) of exosomes can be modulated by engineering various factors such as cellular origin and membrane protein composition of exosomes. Recent advances accentuate the potential of targeted delivery of engineered exosomes even to the most challenging organs including the central nervous system. Major breakthroughs have been made related to various imaging techniques for monitoring in vivo biodistribution and PK of exosomes, as well as exosomal surface engineering technologies for inducing targetability. For inducing targeted delivery, therapeutic exosomes can be engineered to express various targeting moieties via direct modification methods such as chemically modifying exosomal surfaces with covalent/non-covalent bonds, or via indirect modification methods by genetically engineering exosome-producing cells. In this review, we describe the current knowledge of biodistribution and PK of exosomes, factors determining the targetability and organotropism of exosomes, and imaging technologies to monitor in vivo administered exosomes. In addition, we highlight recent advances in strategies for inducing targeted delivery of exosomes to specific organs and cells.

Mononuclear phagocytes as a target, not a barrier, for drug delivery

Yong, Seok-Beom,Song, Yoonsung,Kim, Hyung Jin,Ain, Qurrat Ul,Kim, Yong-Hee Elsevier 2017 Journal of controlled release Vol.259 No.-

<P><B>Abstract</B></P> <P>Mononuclear phagocytes have been generally recognized as a barrier to drug delivery. Recently, a new understanding of mononuclear phagocytes (MPS) ontogeny has surfaced and their functions in disease have been unveiled, demonstrating the need for re-evaluation of perspectives on mononuclear phagocytes in drug delivery. In this review, we described mononuclear phagocyte biology and focus on their accumulation mechanisms in disease sites with explanations of monocyte heterogeneity. In the ‘MPS as a barrier’ section, we summarized recent studies on mechanisms to avoid phagocytosis based on two different biological principles: protein adsorption and self-recognition. In the ‘MPS as a target’ section, more detailed descriptions were given on mononuclear phagocyte-targeted drug delivery systems and their applications to various diseases. Collectively, we emphasize in this review that mononuclear phagocytes are potent targets for future drug delivery systems. Mononuclear phagocyte-targeted delivery systems should be created with an understanding of mononuclear phagocyte ontogeny and pathology. Each specific subset of phagocytes should be targeted differently by location and function for improved disease-drug delivery while avoiding RES clearance such as Kupffer cells and splenic macrophages.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Controlled release and targeted drug delivery with poly(lactic-co-glycolic acid) nanoparticles: reviewing two decades of research

ZEB ALAM,Gul Maleeha,Nguyen Thi-Thao-Linh,맹한주 한국약제학회 2022 Journal of Pharmaceutical Investigation Vol.52 No.6

Background Controlled release and targeted delivery of the drug payload are the two most fascinating applications of nanoparticle-based systems explored in the recent past. The advantages of achieving control over drug release kinetics include prolonged therapeutic effects, reduced dosing frequency, and fewer plasma level fluctuations and side effects, whereas targeted delivery offers enhanced drug accumulation at the site of action and reduced off-target toxicity, thereby improving the management of chronic diseases. Poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) hold tremendous promise for such applications because of their ability to modulate drug release, pharmacokinetics, the biodistribution profiles of drugs, and the surface functionalization for targeted delivery. Area covered This review primarily highlights the applications of PLGA-NPs based on the controlled release of therapeutics after oral, parenteral, pulmonary, ocular, intranasal, and dermal administration and tissue engineering. The potential of PLGA-NPs for targeted delivery to various diseases, such as cancer, rheumatoid arthritis, inflammatory bowel disease, and neurological disorders, has also been extensively reviewed. This review concludes with a description of the limitations of PLGA-NPs and the hurdles associated with their clinical application. Expert opinion PLGA-NPs stand out among other nanoparticles because of their excellent biocompatibility and biodegradability. Although the presented data suggest that they are the major shareholders in controlled-release and targeted-delivery systems, no PLGA-NP formulation has reached clinics. Therefore, further insights into the rational design of PLGA-NPs and clinically relevant testing are required to narrow the gap between the bench and bedside realities.

Biocompatible gelatin nanoparticles for tumor-targeted delivery of polymerized siRNA in tumor-bearing mice

Lee, So Jin,Yhee, Ji Young,Kim, Sun Hwa,Kwon, Ick Chan,Kim, Kwangmeyung Elsevier 2013 Journal of controlled release Vol.172 No.1

<P><B>Abstract</B></P> <P>Structural modifications of the siRNA backbone improved its physiochemical properties for incorporating in gene carriers without loss of gene-silencing efficacy. These modifications provide a wider variety of choice of vector systems for siRNA delivery. We developed a tumor-targeted siRNA delivery system using polymerized siRNA (poly-siRNA) and natural polymer gelatin. The polymerized siRNA (poly-siRNA) was prepared through self-polymerization of thiol groups at the 5′-end of sense and anti-sense strands of siRNA and was encapsulated in the self-assembled thiolated gelatin (tGel) nanoparticles (NPs) with chemical cross-linking. The resulting poly-siRNA-tGel (psi-tGel) nanoparticles (average of 145nm in diameter) protect siRNA molecules from enzymatic degradation, and can be reversibly reduced to release functional siRNA molecules in reductive conditions. The psi-tGel NPs presented efficient siRNA delivery in red fluorescence protein expressing melanoma cells (RFP/B16F10) to down-regulate target gene expression. In addition, the NPs showed low toxicity at a high transfection dose of 125μg/mlpsi-tGel NPs, which included 1μM of siRNA molecules. In tumor-bearing mice, the psi-tGel NPs showed 2.8 times higher tumor accumulation than the naked poly-siRNA, suggesting tumor-targeted siRNA delivery of psi-tGel NPs. Importantly, the psi-tGel NPs induced effective tumor RFP gene silencing <I>in vivo</I> without remarkable toxicity. The psi-tGel NPs have great potential for a systemic siRNA delivery system for cancer therapy, based on their characteristics of low toxicity, tumor accumulation, and effective siRNA delivery.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Target-Specific Gene Silencing of Layer-by-Layer Assembled Gold–Cysteamine/siRNA/PEI/HA Nanocomplex

Lee, Min-Young,Park, Sang-Jun,Park, Kitae,Kim, Ki Su,Lee, Hwiwon,Hahn, Sei Kwang American Chemical Society 2011 ACS NANO Vol.5 No.8

<P>Target-specific intracellular delivery of small interfering RNA (siRNA) is regarded as one of the most important technologies for the development of siRNA therapeutics. In this work, a cysteamine modified gold nanoparticles (AuCM)/siRNA/polyethyleneimine (PEI)/hyaluronic acid (HA) complex was successfully developed using a layer-by-layer method for target-specific intracellular delivery of siRNA by HA receptor mediated endocytosis. Atomic force microscopic and zeta potential analyses confirmed the formation of a AuCM/siRNA/PEI/HA complex having a particle size of <I>ca.</I> 37.3 nm and a negative surface charge of <I>ca.</I> −12 mV. With a negligible cytotoxicity, AuCM/siRNA/PEI/HA complex showed an excellent target-specific gene silencing efficiency of <I>ca.</I> 70% in the presence of 50 vol % serum, which was statistically much higher than that of siRNA/Lipofectamine 2000 complex. In the competitive binding tests with free HA, dark-field bioimaging and inductively coupled plasma–atomic emission spectroscopy confirmed the target-specific intracellular delivery of AuCM/siRNA/PEI/HA complex to B16F1 cells with HA receptors. Moreover, the systemic delivery of AuCM/siRNA/PEI/HA complex using apolipoprotein B (ApoB) siRNA as a model drug resulted in a significantly reduced ApoB mRNA level in the liver tissue. Taken together, AuCM/siRNA/PEI/HA complex was thought to be developed as target-specific siRNA therapeutics for the systemic treatment of various liver diseases.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2011/ancac3.2011.5.issue-8/nn2017793/production/images/medium/nn-2011-017793_0009.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/nn2017793'>ACS Electronic Supporting Info</A></P>

Development of a real time imaging-based guidance system of magnetic nanoparticles for targeted drug delivery

Zhang, Xingming,Le, Tuan-Anh,Yoon, Jungwon Elsevier 2017 Journal of magnetism and magnetic materials Vol.427 No.-

<P><B>Abstract</B></P> <P>Targeted drug delivery using magnetic nanoparticles is an efficient technique as molecules can be directed toward specific tissues inside a human body. For the first time, we implemented a real-time imaging-based guidance system of nanoparticles using untethered electro-magnetic devices for simultaneous guiding and tracking. In this paper a low-amplitude-excitation-field magnetic particle imaging (MPI) is introduced. Based on this imaging technology, a hybrid system comprised of an electromagnetic actuator and MPI was used to navigate nanoparticles in a non-invasive way. The real-time low-amplitude-excitation-field MPI and electromagnetic actuator of this navigation system are achieved by applying a time-division multiplexing scheme to the coil topology. A one dimensional nanoparticle navigation system was built to demonstrate the feasibility of the proposed approach and it could achieve a 2Hz navigation update rate with the field gradient of 3.5T/m during the imaging mode and 8.75T/m during the actuation mode. Particles with both 90nm and 5nm diameters could be successfully manipulated and monitored in a tube through the proposed system, which can significantly enhance targeting efficiency and allow precise analysis in a real drug delivery.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A real-time system comprised of an electromagnetic actuator and a low-amplitude-excitation-field MPI can navigate magnetic nanoparticles. </LI> <LI> The imaging scheme is feasible to enlarge field of view size. </LI> <LI> The proposed navigation system can be cost efficient, compact, and optimized for targeting of the nanoparticles. </LI> </UL> </P>

Evaluation of Dynamic Delivery Quality Assurance Process for Internal Target Volume Based RapidArc

Song, Ju-Young Korean Society of Medical Physics 2017 의학물리 Vol.28 No.4

The conventional delivery quality assurance (DQA) process for RapidArc (Varian Medical Systems, Palo Alto, USA), has the limitation that it measures and analyzes the dose in a phantom material and cannot analyze the dosimetric changes under the motional organ condition. In this study, a DQA method was designed to overcome the limitations of the conventional DQA process for internal target volume (ITV) based RapidArc. The dynamic DQA measurement device was designed with a moving phantom that can simulate variable target motions. The dose distribution in the real volume of the target and organ-at-risk (OAR)s were reconstructed using 3DVH with the ArcCHECK (SunNuclear, Melbourne, USA) measurement data under the dynamic condition. A total of 10 ITV-based RapidArc plans for liver-cancer patients were analyzed with the designed dynamic DQA process. The average pass rate of gamma evaluation was $81.55{\pm}9.48%$ when the DQA dose was measured in the respiratory moving condition of the patient. Appropriate method was applied to correct the effect of moving phantom structures in the dose calculation, and DVH data of the real volume of target and OARs were created with the recalculated dose by the 3DVH program. We confirmed the valid dose coverage of a real target volume in the ITV-based RapidArc. The variable difference of the DVH of the OARs showed that dose variation can occur differently according to the location, shape, size and motion range of the target. The DQA process devised in this study can effectively evaluate the DVH of the real volume of the target and OARs in a respiratory moving condition in addition to the simple verification of the accuracy of the treatment machine. This can be helpful to predict the prognosis of treatment by the accurate dose analysis in the real target and OARs.

A Novel Scheme for Nanoparticle Steering in Blood Vessels Using a Functionalized Magnetic Field

Tehrani, Mohammad Dadkhah,Yoon, Jong-Hwan,Kim, Myeong Ok,Yoon, Jungwon IEEE 2015 IEEE Transactions on Biomedical Engineering Vol.62 No.1

<P>Magnetic drug targeting is a drug delivery approach in which therapeutic magnetizable particles are injected, generally into blood vessels, and magnets are then used to guide and concentrate them in the diseased target organ. Although many analytical, simulation, and experimental studies on capturing schemes for drug targeting have been conducted, there are few studies on delivering the nanoparticles to the target region. Furthermore, the sticking phenomenon of particles to vessels walls near the injection point, and far from the target region, has not been addressed sufficiently. In this paper, the sticking issue and its relationship to nanoparticle steering are investigated in detail using numerical simulations. For wide ranges of blood vessel size, blood velocity, particle size, and applied magnetic field, three coefficient numbers are uniquely generalized: vessel elongation, normal exit time, and force rate. With respect these new parameters, we investigated particle distribution trends for a Y-shaped channel and computed ratios of correctly guided particles and particles remaining in the vessel. We found that the sticking of particles to vessels occurred because of low blood flow velocity near the vessel walls, which is the main reason for low targeting efficiency when using a constant magnetic gradient. To reduce the sticking ratio of nanoparticles, we propose a novel field function scheme that uses a simple time-varying function to separate the particles from the walls and guide them to the target point. The capabilities of the proposed scheme were examined by several simulations of both Y-shaped channels and realistic three-dimensional (3-D) model channels extracted from brain vessels. The results showed a significant decrease in particle adherence to walls during the delivery stage and confirmed the effectiveness of the proposed magnetic field function method for steering nanoparticles for targeted drug delivery.</P>

Bioimaging for Targeted Delivery of Hyaluronic Acid Derivatives to the Livers in Cirrhotic Mice Using Quantum Dots

Kim, Ki Su,Hur, Wonhee,Park, Sang-Jun,Hong, Sung Woo,Choi, Jung Eun,Goh, Eun Ji,Yoon, Seung Kew,Hahn, Sei Kwang American Chemical Society 2010 ACS NANO Vol.4 No.6

<P>Liver fibrosis or cirrhosis is one of the representative liver diseases with a high morbidity and mortality worldwide. Over the past decades, many kinds of antifibrotic compounds have been investigated <I>in vitro</I> and <I>in vivo</I> for the treatment of liver cirrhosis. In this work, real-time bioimaging of hyaluronic acid (HA) derivatives was carried out using quantum dots (QDots) to assess the possibility of HA derivatives as target-specific drug delivery carriers for the treatment of liver diseases. HA-QDot conjugates with an HA modification degree of about 22 mol % was synthesized by amide bond formation between carboxyl groups of QDots and amine groups of adipic acid dihydrazide modified HA (HA-ADH). According to <I>in vitro</I> cell culture tests, HA-QDot conjugates were taken up more to the cells causing chronic liver diseases such as hepatic stellate cells (HSC-T6) and hepatoma cells (HepG2) than normal hepatocytes (FL83B). After tail-vein injection, HA-QDot conjugates were target-specific, being delivered to the cirrhotic liver with a slow clearance longer than 8 days. Furthermore, immunofluorescence and flow cytometric analyses of dissected liver tissues revealed the target-specific delivery of HA derivatives to liver sinusoidal endothelial cells (LSEC) and HSC. The results were thought to reflect the feasibility of HA derivatives as novel drug delivery carriers for the treatment of various chronic liver diseases including hepatitis, liver cirrhosis, and liver cancer.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2010/ancac3.2010.4.issue-6/nn100589y/production/images/medium/nn-2010-00589y_0010.gif'></P>