Vaccine-Induced Immunity Elicited by Microneedle Delivery of Influenza Ectodomain Matrix Protein 2 Virus-like Particle (M2e VLP)-Loaded PLGA Nanoparticles.

This study focused on developing an influenza vaccine delivered in polymeric nanoparticles (NPs) using dissolving microneedles. We first formulated an influenza extracellular matrix protein 2 virus-like particle (M2e VLP)-loaded with poly(lactic-co-glycolic) acid (PLGA) nanoparticles, yielding M2e5x VLP PLGA NPs. The vaccine particles were characterized for their physical properties and in vitro immunogenicity. Next, the M2e5x VLP PLGA NPs, along with the adjuvant Alhydrogel® and monophosphoryl lipid A® (MPL-A®) PLGA NPs, were loaded into fast-dissolving microneedles. The vaccine microneedle patches were then evaluated in vivo in a murine model. The results from this study demonstrated that the vaccine nanoparticles effectively stimulated antigen-presenting cells in vitro resulting in enhanced autophagy, nitric oxide, and antigen presentation. In mice, the vaccine elicited M2e-specific antibodies in both serum and lung supernatants (post-challenge) and induced significant expression of CD4+ and CD8+ populations in the lymph nodes and spleens of immunized mice. Hence, this study demonstrated that polymeric particulates for antigen and adjuvant encapsulation, delivered using fast-dissolving microneedles, significantly enhanced the immunogenicity of a conserved influenza antigen.

Nanoparticle encapsulated oxytocin increases resistance to induced seizures and restores social behavior in Scn1a-derived epilepsy.

Oxytocin (OT) has broad effects in the brain and plays an important role in cognitive, social, and neuroendocrine function. OT has also been identified as potentially therapeutic in neuropsychiatric disorders such as autism and depression, which are often comorbid with epilepsy, raising the possibility that it might confer protection against the behavioral and seizure phenotypes in epilepsy. Dravet syndrome (DS) is an early-life encephalopathy associated with prolonged and recurrent early-life febrile seizures (FSs), treatment-resistant afebrile epilepsy, and cognitive and behavioral deficits. De novo loss-of-function mutations in the voltage-gated sodium channel SCN1A are the main cause of DS, while genetic epilepsy with febrile seizures plus (GEFS+), also characterized by early-life FSs and afebrile epilepsy, is typically caused by inherited mutations that alter the biophysical properties of SCN1A. Despite the wide range of available antiepileptic drugs, many patients with SCN1A mutations do not achieve adequate seizure control or the amelioration of associated behavioral comorbidities. In the current study, we demonstrate that nanoparticle encapsulation of OT conferred robust and sustained protection against induced seizures and restored more normal social behavior in a mouse model of Scn1a-derived epilepsy. These results demonstrate the ability of a nanotechnology formulation to significantly enhance the efficacy of OT. This approach will provide a general strategy to enhance the therapeutic potential of additional neuropeptides in epilepsy and other neurological disorders.

Formulation and Characterization of Microcapsules Encapsulating PC12 Cells as a Prospective Treatment Approach for Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurological disorder, associated with decreased dopamine levels in the brain. The goal of this study was to assess the potential of a regenerative medicine-based cell therapy approach to increase dopamine levels. In this study, we used rat adrenal pheochromocytoma (PC12) cells that can produce, store, and secrete dopamine. These cells were microencapsulated in the selectively permeable polymer membrane to protect them from immune responses. For fabrication of the microcapsules, we used a modified Buchi spray dryer B-190 that allows for fast manufacturing of microcapsules and is industrially scalable. Size optimization of the microcapsules was performed by systematically varying key parameters of the spraying device. The short- and long-term stabilities of the microcapsules were assessed. In the in vitro study, the cells were found viable for a period of 30 days. Selective permeability of the microcapsules was confirmed via dopamine release assay and micro BCA protein assay. We found that the microcapsules were permeable to the small molecules including dopamine and were impermeable to the large molecules like BSA. Thus, they can provide the protection to the encapsulated cells from the immune cells. Griess's assay confirmed the non-immunogenicity of the microcapsules. These results demonstrate the effective fabrication of microcapsules encapsulating cells using an industrially scalable device. The microcapsules were stable, and the cells were viable inside the microcapsules and were found to release dopamine. Thus, these microcapsules have the potential to serve as the alternative or complementary treatment approach for PD.

Nanoparticle encapsulation increases the brain penetrance and duration of action of intranasal oxytocin.

The blood-brain barrier (BBB) limits the therapeutic use of large molecules as it prevents them from passively entering the brain following administration by conventional routes. It also limits the capacity of researchers to study the role of large molecules in behavior, as it often necessitates intracerebroventricular administration. Oxytocin is a large-molecule neuropeptide with pro-social behavioral effects and therapeutic promise for social-deficit disorders. Although preclinical and clinical studies are using intranasal delivery of oxytocin to improve brain bioavailability, it remains of interest to further improve the brain penetrance and duration of action of oxytocin, even with intranasal administration. In this study, we evaluated a nanoparticle drug-delivery system for oxytocin, designed to increase its brain bioavailability through active transport and increase its duration of action through encapsulation and sustained release. We first evaluated transport of oxytocin-like large molecules in a cell-culture model of the BBB. We then determined in vivo brain transport using bioimaging and cerebrospinal fluid analysis in mice. Finally, we determined the pro-social effects of oxytocin (50 µg, intranasal) in two different brain targeting and sustained-release formulations. We found that nanoparticle formulation increased BBB transport both in vitro and in vivo. Moreover, nanoparticle-encapsulated oxytocin administered intranasally exhibited greater pro-social effects both acutely and 3 days after administration, in comparison to oxytocin alone, in mouse social-interaction experiments. These multimodal data validate this brain targeting and sustained-release formulation of oxytocin, which can now be used in animal models of social-deficit disorders as well as to enhance the brain delivery of other neuropeptides.

Evaluation of an adjuvanted hydrogel-based pDNA nanoparticulate vaccine for rabies prevention and immunocontraception.

Immunocontraceptive vaccination is becoming an acceptable strategy in managing animal populations. Mass vaccination of dogs is the most cost-effective and efficient method to control rabies, and combination of rabies vaccination and animal population control will be an added advantage. In this study, we developed an adjuvanted hydrogel-based pDNA nanoparticulate vaccine for rabies protection and immunocontraception. In vivo, we observed an immune response skewed toward a Th2 type, in contrast to the Th1 type in our previous pDNA study. The observation was verified by the IgG2a/IgG1 ratio (<1), and cytokine expression profile of IL-4 and IFN-γ. The humoral immune response is key for rabies protection and a GnRH antibody-based immunocontraception. In mice, anti-GnRH antibody titers were detected 4 weeks after immunization and lasted for 12 weeks, post animal experiment was terminated. The adjuvanted pDNA nanoparticulate vaccine shows promise for future studies evaluating protection from rabies challenge and prevention of animal breeding.

Pulmonary Administration of Microparticulate Antisense Oligonucleotide (ASO) for the Treatment of Lung Inflammation.

Targeted delivery to the lung for controlling lung inflammation is an area that we have explored in this study. The purpose was to use microparticles containing an antisense oligonucleotide (ASO) to NF-κB to inhibit the production of proinflammatory cytokines. Microparticles were prepared using the B-290 Buchi Spray Dryer using albumin as the microparticle matrix. Physicochemical characterization of the microparticles showed the size ranged from 2 to 5 µm, the charge was - 38.4 mV, and they had a sustained release profile over 72 h. Uptake of FITC-labeled ASO-loaded microparticles versus FITC-labeled ASO solution by RAW264.7 murine macrophage cells was 5-10-fold higher. After pulmonary delivery of microparticles to Sprague-Dawley rats, the microparticles were uniformly distributed throughout the lung and were retained in the lungs until 48 h. Serum cytokine (TNF-α and IL-1ß) levels of rats after induction of lung inflammation by lipopolysaccharide were measured until 72 h. Animals receiving ASO-loaded microparticles were successful in significantly controlling lung inflammation during this period as compared to animals receiving no treatment. This study was successful in proving that microparticulate ASO therapy was capable of controlling lung inflammation.

Physicochemical and Preclinical Evaluation of a Novel Buccal Measles Vaccine.

The aim of this study is to develop an orally disintegrating film (ODF) containing a microparticulate measles vaccine formulation for buccal delivery. The measles vaccine microparticles were made with biocompatible and biodegradable bovine serum albumin (BSA) and processed by spray drying. These vaccine microparticles were incorporated in the ODF, consisting of Lycoat RS720®, Neosorb P60W® and Tween 80. The yield of the microparticles was approximately 85-95%, w/w. The mean size of the vaccine microparticles was 3.65 ± 1.89 µm and had a slightly negative surface charge of 32.65 ± 2.4 mV. The vaccine particles were nontoxic to normal cells at high concentrations (500 µg/2.5 × 105 cells) of vaccine particles. There was a significant induction of innate immune response by vaccine microparticles which was observed in vitro when compared to blank microparticles (P < 0.05). The vaccine microparticles also significantly increased the antigen presentation and co-stimulatory molecules expression on antigen presenting cells, which is a prerequisite for Th1 and Th2 immune responses. When the ODF vaccine formulation was dosed in juvenile pigs, significantly higher antibody titers were observed after week 2, with a significant increase at week 4 and plateauing through week 6 comparative to naïve predose titers. The results suggest that the ODF measles vaccine formulation is a viable dosage form alternative to noninvasive immunization that may increase patient compliance and commercial distribution.

Development of a microparticulate prostate cancer vaccine and evaluating the effect of route of administration on its efficacy via the skin.

The skin has been identified as a promising target to deliver vaccines. In this study, prostate cancer antigens were delivered in a spray-dried microparticulate carrier to a murine model via the transdermal route and the subcutaneous route. There was a significant increase in the humoral responses as determined by the total serum IgG titres (p < 0.05) and the cellular responses as determined by the T- and B-cells sub-population in spleen samples and delay in tumour growth till 8 weeks post-tumour challenge of both vaccinated groups when compared to the controls. The vaccine microparticles administered via the transdermal route induced a Th2-mediated immune response versus a mixed Th1- and Th2-mediated immune response via the subcutaneous route. Thus, the particulate vaccine delivery system proves to be a promising alternative for generation of a robust immune response against prostate cancer via the skin in a murine model.

Intranasal Immunization for Zika in a Pre-Clinical Model.

Humans continue to be at risk from the Zika virus. Although there have been significant research advancements regarding Zika, the absence of a vaccine or approved treatment poses further challenges for healthcare providers. In this study, we developed a microparticulate Zika vaccine using an inactivated whole Zika virus as the antigen that can be administered pain-free via intranasal (IN) immunization. These microparticles (MP) were formulated using a double emulsion method developed by our lab. We explored a prime dose and two-booster-dose vaccination strategy using MPL-A® and Alhydrogel® as adjuvants to further stimulate the immune response. MPL-A® induces a Th1-mediated immune response and Alhydrogel® (alum) induces a Th2-mediated immune response. There was a high recovery yield of MPs, less than 5 µm in size, and particle charge of -19.42 ± 0.66 mV. IN immunization of Zika MP vaccine and the adjuvanted Zika MP vaccine showed a robust humoral response as indicated by several antibodies (IgA, IgM, and IgG) and several IgG subtypes (IgG1, IgG2a, and IgG3). Vaccine MP elicited a balance Th1- and Th2-mediated immune response. Immune organs, such as the spleen and lymph nodes, exhibited a significant increase in CD4+ helper and CD8+ cytotoxic T-cell cellular response in both vaccine groups. Zika MP vaccine and adjuvanted Zika MP vaccine displayed a robust memory response (CD27 and CD45R) in the spleen and lymph nodes. Adjuvanted vaccine-induced higher Zika-specific intracellular cytokines than the unadjuvanted vaccine. Our results suggest that more than one dose or multiple doses may be necessary to achieve necessary immunological responses. Compared to unvaccinated mice, the Zika vaccine MP and adjuvanted MP vaccine when administered via intranasal route demonstrated robust humoral, cellular, and memory responses. In this pre-clinical study, we established a pain-free microparticulate Zika vaccine that produced a significant immune response when administered intranasally.

Implementation of mixture design for formulation of albumin containing enteric-coated spray-dried microparticles.

CONTEXT: Oral delivery of proteins has been a challenging as well as rapidly developing field. OBJECTIVE: To implement mixture design of experiment to develop enteric-coated microparticles containing bovine serum albumin. MATERIALS AND METHODS: Microparticles were prepared using Buchi Spray Dryer 191. Simplex lattice mixture design computed using JMP software was implemented to compare the gastric protection rendered by Eudragit FS30D, Eudragit L100-55, and Eudragit S100 in microparticulate form. Further, an extreme vertices mixture design was used to incorporate hydroxypropyl methylcellulose (HPMC) Chitosan in the formulation to delay the release. Microparticle recovery yield and protein content in microparticles were evaluated. RESULTS AND DISCUSSIONS: The design was statistically significant with Eudragit S100 resulting in protein release of < 5% in acidic buffer. The selected optimal formulation had 70% of Eudragit S, 25% HPMC, and 5% Chitosan. The release profiles of protein from Eudragit S alone and along with HPMC were compared. About 25% decrease in the amount of protein release was observed 6 h post exposure of microparticle to buffer of pH 6.8. The microparticle recovery yield reduced from 77.99% to 71.56% which is due to addition of HPMC into the formulation matrix. CONCLUSION: Although all three Eudragit polymers can be used for enteric coating, in the microparticulate form Eudragit S resulted in higher gastric protection. Also use of HPMC along with Eudragit S resulted in further sustained release.

Microencapsulation of protein into biodegradable matrix: a smart solution cross-linking technique.

Sustained-release albumin microspheres (MSs) can be obtained by chemically cross-linking albumin. However, a significant challenge is preventing the cross-linking of the active pharmaceutical (protein or small molecule) ingredient (API) with the MS matrix. To prevent cross-linking of the API with the albumin matrix, a smart "solution cross-linking-microencapsulation" method was developed which involves cross-linking albumin solution with glutaraldehyde first, neutralizing any excess glutaraldehyde with sodium bisulphite, followed by the addition of API and finally spray drying. Using lysozyme as model API, MS formulations FL1 and FL2 were prepared and characterized. Physicochemical characterization using FT-IR and bioactivity evaluation indicate that microencapsulated API did not undergo any significant change in its native structure and the bioactivity was preserved during the formulation processing. Preliminary immunogenicity potential of the cross-linked albumin matrix determined by in vivo studies did not show any significant increase in antigen-specific serum-IgG levels, implying safety and biocompatibility of the cross-linked albumin matrix.

Formulation of meningococcal capsular polysaccharide vaccine-loaded microparticles with robust innate immune recognition.

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis associated with a high mortality rate. Capsular polysaccharides (CPSs) are a major virulence factor and form the basis for serogroup designation and protective vaccines. The current polysaccharide meningococcal vaccines are available but are very expensive and require chemical conjugation. Here, we report a novel meningococcal vaccine formulation consisting of meningococcal CPS polymers encapsulated in albumin-based biodegradable microparticles that slowly release antigen and induce robust innate immune responses. Vaccines that elicit innate immunity are reported to have enhanced and protective adaptive immune responses. In this study, the meningococcal CPS-loaded microparticles, but not the empty microparticles, induced the release of IL-8, TNF-α and IL-1ß, enhanced phagocytic capacity and induced robust autophagy in macrophages. The novel meningococcal vaccine microparticles are robustly taken up by macrophages and elicit strong innate immune responses that enhance antigen presentation which is a prerequisite for inducing adaptive immunity.

Boosting In-Vivo Anti-Tumor Immunity with an Oral Microparticulate Breast Cancer Vaccine and Low-Dose Cyclophosphamide.

Tumor cells express antigens that should induce immune-mediated rejection; however, spontaneous rejection of established tumors is rare. Recent evidence suggests that patients suffering from cancer exhibit an elevation in regulatory T cells population, a subset of CD4+ T cells, which suppress tumor recognition and elimination by cytotoxic T cells. This study investigates immunotherapeutic strategies to overcome the immunosuppressive effects exerted by regulatory T cells. A novel immunotherapeutic strategy was developed by simultaneous administration of oral microparticulate breast cancer vaccines and cyclophosphamide, a regulatory T cell inhibitor. Breast cancer vaccine microparticles were prepared by spray drying, and administered orally to female mice inoculated with 4TO7 murine breast cancer cells in combination with a low dose of intraperitoneally administered cyclophosphamide. Mice receiving the combination of vaccine microparticles and cyclophosphamide exhibited maximal tumor regression and the highest survival rate compared with the control groups. This study highlights the importance of cancer vaccination along with regulatory T cell depletion in cancer therapy, and suggests that a low dose of cyclophosphamide that specifically and significantly depletes regulatory T cells may be a highly effective immunotherapeutic strategy for the treatment of cancer.

Adjuvanted-SARS-CoV-2 Spike Protein-Based Microparticulate Vaccine Delivered by Dissolving Microneedles Induces Humoral, Mucosal, and Cellular Immune Responses in Mice.

COVID-19 continues to cause an increase in the number of cases and deaths worldwide. Due to the ever-mutating nature of the virus, frequent vaccination against COVID-19 is anticipated. Most of the approved SARS-CoV-2 vaccines are administered using the conventional intramuscular route, causing vaccine hesitancy. Thus, there is a need for an effective, non-invasive vaccination strategy against COVID-19. This study evaluated the synergistic effects of a subunit microparticulate vaccine delivered using microneedles. The microparticles encapsulated a highly immunogenic subunit protein of the SARS-CoV-2 virus, such as the spike protein's receptor binding domain (RBD). Adjuvants were also incorporated to enhance the spike RBD-specific immune response. Our vaccination study reveals that a microneedle-based vaccine delivering these microparticles induced spike RBD-specific IgM, IgG, IgG1, IgG2a, and IgA antibodies. The vaccine also generated high levels of CD4+ and CD8a+ molecules in the secondary lymphoid organs. Overall, dissolving microneedles delivery spike RBD antigen in microparticulate form induced a robust immune response, paving the way for an alternative self-administrable, non-invasive vaccination strategy against COVID-19.

Subunit microparticulate vaccine delivery using microneedles trigger significant SARS-spike-specific humoral and cellular responses in a preclinical murine model.

The objective of this "proof-of-concept" study was to evaluate the synergistic effect of a subunit microparticulate vaccine and microneedles (MN) assisted vaccine delivery system against a human coronavirus. Here, we formulated PLGA polymeric microparticles (MPs) encapsulating spike glycoprotein (GP) of SARS-CoV as the model antigen. Similarly, we formulated adjuvant MPs encapsulating Alhydrogel® and AddaVax™. The antigen/adjuvant MPs were characterized and tested in vitro for immunogenicity. We found that the antigen/adjuvant MPs were non-cytotoxic in vitro. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs showed enhanced immunogenicity in vitro as confirmed through the release of nitrite, autophagy, and antigen presenting molecules with their co-stimulatory molecules. Next, we tested the in vivo efficacy of the spike GP MP vaccine with and without adjuvant MPs in mice vaccinated using MN. The spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs induced heightened spike GP-specific IgG, IgG1 and IgG2a antibodies in mice. Also, spike GP MPs + Alhydrogel® MPs + AddaVax™ MPs enhanced expression of CD4+ and CD8+ T cells in secondary lymphoid organ like spleen. These results indicated spike GP-specific humoral immunity and cellular immunity in vivo. Thus, we employed the benefits of both the subunit vaccine MPs and dissolving MN to form a non-invasive and effective vaccination strategy against human coronaviruses.

Gonococcal microparticle vaccine in dissolving microneedles induced immunity and enhanced bacterial clearance in infected mice.

There is an alarming rise in the number of gonorrhea cases worldwide. Neisseria gonorrhoeae, the bacteria that causes gonorrhea infection, has gradually developed antimicrobial resistance over the years. To date, there is no licensed vaccine for gonorrhea. This study investigates the in vivo immunogenicity of a whole-cell inactivated gonococci in a microparticle formulation (Gc-MP) along with adjuvant microparticles (Alhydrogel®- Alum MP and AddaVax™ MP) delivered transdermally using dissolving microneedles (MN). The proposed vaccine formulation (Gc-MP + Alum MP + AddaVax™ MP) was assessed for induction of humoral, cellular, and protective immune responses in vivo. Our results show the induction of significant gonococcal-specific serum IgG, IgG1, IgG2a, and vaginal mucosal IgA antibodies in mice immunized with Gc-MP + Alum MP + AddaVax™ MP and Gc-MP when compared to the control groups receiving blank MN or no treatment. The serum bactericidal assay revealed that the antibodies generated in mice after immunization with Gc-MP + Alum MP + AddaVax™ MP were bactericidal towards live Neisseria gonorrhoeae. Gc-MP + Alum MP + AddaVax™ MP and Gc-MP-immunized mice showed enhanced clearance rate of gonococcal bacterial infection post challenge. In contrast, the control groups did not begin to clear the infection until day 10. In addition, the mice which received Gc-MP + Alum MP + AddaVax™ MP showed enhanced expression of cellular immunity markers CD4 and CD8 on the surface of T cells in the spleen and lymph nodes. Taken together, the data shows that microneedle immunization with whole-cell inactivated gonococci MP in mice induced humoral, cellular, and protective immunity against gonococcal infection.

An Adjuvanted Inactivated SARS-CoV-2 Microparticulate Vaccine Delivered Using Microneedles Induces a Robust Immune Response in Vaccinated Mice.

SARS-CoV-2, the causal agent of COVID-19, is a contagious respiratory virus that frequently mutates, giving rise to variant strains and leading to reduced vaccine efficacy against the variants. Frequent vaccination against the emerging variants may be necessary; thus, an efficient vaccination system is needed. A microneedle (MN) vaccine delivery system is non-invasive, patient-friendly, and can be self-administered. Here, we tested the immune response produced by an adjuvanted inactivated SARS-CoV-2 microparticulate vaccine administered via the transdermal route using a dissolving MN. The inactivated SARS-CoV-2 vaccine antigen and adjuvants (Alhydrogel® and AddaVax™) were encapsulated in poly(lactic-co-glycolic acid) (PLGA) polymer matrices. The resulting MP were approximately 910 nm in size, with a high percentage yield and percent encapsulation efficiency of 90.4%. In vitro, the vaccine MP was non-cytotoxic and increased the immunostimulatory activity measured as nitric oxide release from dendritic cells. The adjuvant MP potentiated the immune response of the vaccine MP in vitro. In vivo, the adjuvanted SARS-CoV-2 MP vaccine induced high levels of IgM, IgG, IgA, IgG1, and IgG2a antibodies and CD4+ and CD8+ T-cell responses in immunized mice. In conclusion, the adjuvanted inactivated SARS-CoV-2 MP vaccine delivered using MN induced a robust immune response in vaccinated mice.

Zika Vaccine Microparticles (MPs)-Loaded Dissolving Microneedles (MNs) Elicit a Significant Immune Response in a Pre-Clinical Murine Model.

Although the global Zika epidemic in 2015-16 fueled vaccine development efforts, there is no approved Zika vaccine or treatment available to date. Current vaccine platforms in clinical trials are administered via either subcutaneous or intramuscular injections, which are painful and decrease compliance. Therefore, in the present study, we explored Zika vaccine microparticles (MPs)-loaded dissolving microneedles (MNs) with adjuvant MPs encapsulating Alhydrogel® and MPL-A® administered via the transdermal route as a pain-free vaccine strategy. We characterized the MNs for needle length, pore formation, and dissolvability when applied to murine skin. Further, we evaluated the in vivo efficacy of vaccine MPs-loaded MNs with or without adjuvants by measuring the immune response after transdermal immunization. The vaccine MPs-loaded dissolving MNs with adjuvants induced significant IgG, IgG1, and IgG2a titers in immunized mice compared to the untreated control group. After the dosing regimen, the animals were challenged with Zika virus, monitored for seven days, and sacrificed to collect spleen and lymph nodes. The lymphocytes and splenocytes from the immunized mice showed significant expressions of helper (CD4) and cytotoxic (CD8a) cell surface markers compared to the control group. Thus, this study puts forth a 'proof-of-concept' for a pain-free transdermal vaccine strategy against Zika.

Spray-dried microparticles: a potential vehicle for oral delivery of vaccines.

This study aims to formulate a microparticle-based system that protects the protein from the harsh gastric conditions and also provides appropriate uptake via M cells for desired immune response upon oral administration. The formulation was derived using a valid statistical model, analysed by JMP® (SAS). The average size and charge of the resulting microparticles were 1.51 ± 0.125 µm and + 15.7 ± 2.5 mV, respectively. Moreover, the particles provided a prolonged release over a period of 8 hrs which ensures M-cell uptake of intact particle with antigen (Kunisawa et al., 2011). This was further supported with in vivo studies where particle uptake was found in Peyer's patches of small intestine when observed for 8 h. Thus, these microparticles can be used as an efficient vaccine delivery vehicle upon oral administration.

Microencapsulated drug delivery: a new approach to pro-inflammatory cytokine inhibition.

CONTEXT: This article reviews the use of albumin microcapsules 3-4 µm in size containing cytokine inhibiting drugs which include neutralizing antibodies to TNF and IL1, CNI-1493, antisense oligonucleotides to TNF and NF-kappaB, and the antioxidant catalase. OBJECTIVE: Describe the effects, cellular uptake and distribution of microencapsulated drugs and the effect in both a peritonitis model of infection and a model of adjuvant-induced arthritis. METHODS: The studies performed by our group are reviewed, the only such studies available. RESULTS: Microencapsulation of these compounds produced high intracellular drug concentrations due to rapid uptake by phagocytic cells, including endothelial cells, without toxicity. All compounds produced excellent inhibition of TNF and IL1 resulting in improved animal survival in a peritonitis model of septic shock and inflammation in an arthritis model. CONCLUSION: Albumin microencapsulated pro-inflammatory cytokine inhibiting compounds are superior to equivalent concentration of these compounds administered in solution form.