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Transdermal drug delivery efficacy of hyaluronic acid dissolving microneedles (HA DMNs) is limited by low loading dose and poor drug condensation in needles. HA swelling MNs (HA SMNs) could improve the efficacy, but comparisons between the formulations is missing. In this work, DMNs and SMNs were fabricated of HA and methacrylated HA, respectively. Their properties of transdermal drug delivery were systematically compared. HA SMNs exhibited enhanced mechanical strength, fast swelling performance, and extended duration of microchannels in skin. The doxorubicin (DOX) loaded by one-step loading protocol in needles and baseplate of SMNs could be transdermally delivered through the diffusing path mediated by swollen needles, conquering the limit of poor drug condensation in DMNs needles and generated a longer Tmax but higher Cmax. The relative bioavailability of DOX/SMNs towards DOX/DMNs was 200% within 12 h. The results provide theoretical references for the application of HA MNs mediated transdermal drug delivery., (Copyright © 2021. Published by Elsevier B.V.)

Tumor-draining lymph nodes (TDLN) are major metastatic sites for many solid tumor to support tumor progression and metastasis. Lymphatic delivery is regarded as a desirable route to promote adoptive immune response via vaccination, or to achieve efficient chemotherapy for tumor metastasis. In this study, a novel dissolving microneedle was fabricated using hyaluronic acid, integrated with transfersome (T) to break the limit of transdermal cargo transit. In virtue of the insertion capacity of microneedle and the lymphatic delivering ability of transfersomes, such transfersome/microneedles complex (T/MNs) was expected to enhance lymphatic delivery. The results revealed that the microneedles were able to efficiently insert into rat skin and release the doxorubicin loaded transfersome (DOX-T) in dermis via self-dissolution. DOX-T would maintain their multilayer structure as released from dissolved microneedles. DOX-T/MN could significantly promote accumulation of DOX in lymph nodes compared to epidermal diffusion, and increased its transdermal bioavailability in plasma. The results not only are promising for chemo-therapy of tumor through lymphatic drug delivery, especially for killing the metastasized tumor cells appeared in draining lymph nodes, they also provide an efficient strategy for tumor immune-therapy using transdermal administration., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Here we described nano-polyplexes (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) as novel potential carriers for oral gene vaccines delivery. Aerolysin gene (aerA) of Aeromonas hydrophila as microbial antigen was efficiently loaded to form OCMCS-HA/aerA (OHA) NPs. OHA NPs performed the optimal parameters, i.e. smallest (154.5±9.4nm), positive charged (+7.9±0.5mV) and monodispersed system with the N/P ratio of 5 and OCMCS/HA weight ratio of 4. Upon the introduction of HA, OHA NPs was beneficial for the DNA release in intestinal environments in comparison to OA NPs. The mean fluorescence intensity detected in Caco-2 cells incubated with OHA NPs was about 2.5-fold higher than that of OA NPs; however, it decreased significantly in the presence of excess free HA. The OHA NPs and OA NPs decreased the transepithelial electric resistance (TEER) of Caco-2 monolayers obviously and induced increasing the apparent permeability coefficient (Papp) of DNA by 5.45-6.09 folds compared with free DNA. Significantly higher (P<0.05) antigen-specific antibodies were detected in serum after orally immunized with OHA NPs than that immunized with OA NPs and DNA alone in carps. These results enable the OHA NPs might resolve challenges arising from gastrointestinal damage to gene antigens, and offer an approach applicable for oral vaccination., (Copyright © 2016. Published by Elsevier B.V.)

A novel hyaluronic acid modified transfersome was prepared to deliver drugs to lymphatics through the transdermal route. Doxorubicin loaded HA-GMS-T was able to efficiently penetrate into the deep skin tissue, leading to enhanced absorption by lymphatics. Most importantly, hyaluronic acid effectively improved the uptake of drug loaded nanocarriers by tumor cells.

This study designs an alternative transdermal delivery system for 10,11-methylenedioxycamptothecin(MD-CPT) to inhibit keloid. Hyaluronic acid nanoemulsions (HANs) with nano size, negative charge and good stability were prepared as transdermal carriers. The MD-CPT loaded HANs performed desirable skin permeable capacity across human keloid skin and the drug was transferred directly to keloid lesion area. MD-CPT was delivered percutaneously higher than the control group. FITC-HANs could be successfully internalized by keloid fibroblast (KF) and deliver MD-CPT toward nucleus, inhibited the proliferation of KF, while there was no serious toxicity to normal skin fibroblasts. The growth-inhibitory effect was further clarified upon cell cycle regulation, which arrested cells at G1/S and prevented them entry into mitosis. KF gene expression demonstrated plasminogen activator inhibitor-1 (PAI-1) was significantly down-regulated and Smad7 up-regulated, which was beneficial to inhibit keloid. The study demonstrated that as transdermal delivery of MD-CPT by HANs has potential for inhibition of keloid fibroblast., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To develop a functional nanosized transdermal drug delivery system for tumor therapy, amphiphilic hyaluronic acid (HA) based niosome was constructed combining transdermal and tumor targeting ability in one entity. HA esterified with monostearin, the conjugate labeled as HA-GMS self-assembled onto niosome surface and formed HA-niosome. The multilayer vesicle had small size (around 40 nm), good stability and desirable drug encapsulating efficacy, and well compatible with blood. It exhibited better endocytosis to mouse breast tumor cell (4T1) than the control chitosan nanoparticle, which was verified qualitatively and quantitatively. Skin permeation of HA-niosome was proven to be efficient using in vitro stratum corneum model and in vivo fluorescence observation. Histological section study confirmed the security and efficiency of transdermal permeation. The results evidence HA-niosome to be exciting and promising for tumor therapy through trandermal administration., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The present work described nanoparticles (NPs) made of oleoyl-carboxymethy-chitosan (OCMCS)/hyaluronic acid (HA) using coacervation process as novel potential carriers for gene delivery. An N/P ratio of 5 and OCMCS/HA weight ratio of 4 were the optimal conditions leading to the smallest (164.94 nm), positive charged (+14.2 mV) and monodispersed NPs. OCMCS-HA/DNA (OHD) NPs showed higher in vitro DNA release rates and increased cellular uptake by Caco-2 cells due to the HA involved in NPs. The MTT survival assay indicated no significant cytotoxicity. The transfection efficiency of OHD NPs was 5-fold higher than OCMCS/DNA (OD) NPs; however, it decreased significantly in the presence of excess free HA. The results indicated that OHD NPs internalized in Caco-2 cells were mediated by the hyaluronan receptor CD44. The data obtained in the present research gave evidence of the potential of OHD NPs for the targeting and further transfer of genes to the epithelial cells., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Abstract: An alcohol-free oil/water hyaluronic acid nanoemulsion was developed to be applied as transdermal carrier for active lipophilic ingredient. In vitro hemolysis, skin penetration and histological examinations were carried out using α-tocopherol as model ingredient to assess skin permeability and bioavailability. Without any chemical enhancers, nanoemuslion performed desirable skin permeable capacity, being able to penetrate across stratum corneum and diffuse deeper into dermis compared with the control group (ethanol solution) via follicular and intercellular pathway. Penetration mechanism was preliminarily studied and suggested to be closely concerned with transmembrane concentration gradient, carrier characteristics and penetration enhancers. No irritation has been found in dermis and skin surface indicated hyaluronic acid nanoemulsions could be successfully used as purcutaneous delivery carrier of active lipophilic ingredient and favorable for drug and cosmetic applications. [Copyright &y& Elsevier]

Abstract: In this study, stability of hyaluronic acid (HA) based nanoemulsion was systematically investigated. Factors including zeta potential, pH, crosslinking agents and degree of substitution (DS) were considered to assess their roles in stability. Nanoemulsions prepared from HA-GMS with higher DS showed smaller droplet sizes. In the presence of Ca2+ as a crosslinker, size distribution was improved to be more uniform at the expense of size increases within a controllable range. The optimal amount of Ca2+ usage was determined as 0.05%, which alleviated droplet flocculation and improved morphological qualities as well. Electrostatic, steric, and hydrophobic effects were verified to play crucial roles in emulsion stability. Surfactants strategy was another prerequisite making a key contribution. Encapsulation efficiency (E.E.) study using vitamin E as a model active ingredient proved the eligibility of HA-GMS nanoemulsion exploited as carriers, where the highest E.E. was 93.9±1.4% occurring in sample L6. Fluorescence quenching assay offered evidence of VE encapsulation inside the hydrophobic interior of HA-GMS nanodroplets. [Copyright &y& Elsevier]

Abstract: Hyaluronic acid (HA) was modified into an amphiphile through esterification between the carboxyl and hydroxyl moieties on glycerol-α-monostearate (GMS). The conjugation was verified via FT/IR and 1H NMR. Ultrasonification and solvent evaporation were used to prepare a fine oil/water/surfactant (O/W/S) nanoemulsion consisting of methylene chloride as the oil phase (O), HA water solution (W), and non-ionic Tween-80 and Span-20 as surfactant (S). The optimal ratio of the disperse phase was screened in nanoemulsion formed without HA-GMS. Tween-80 and Span-20 at the required hydrophilic–lipophilic balance (HLB) of 12.5 and a ratio of O/S (ROS) of 60, which accounted for 5% (w/w) in the emulsion system, was determined to be the optimal disperse phase ratio, giving rise to the smallest droplet size (39.7nm) and lower protein dispersibility (0.341). The smallest droplet size of the HA-GMS nanoemulsion was 42.0nm, with contraction to 38.9nm evident after 96h storage. Higher degree of substitution or lower molecular weight was favorable for the formation of smaller emulsified droplets. Nanoemulsions were characterized morphologically by electronic microscopy. [ABSTRACT FROM AUTHOR]

Certain chemo-drugs could induce immunogenic cell death (ICD) activating T cell antitumor immunity while trigger indoleamine-2,3-dioxygenase (IDO) upregulation suppressing immune responses. Moreover, to achieve therapeutic efficacies on both primary tumors and tumor draining lymph nodes (TDLNs) in the meantime is still a big challenge. In this study, transfersomes functionalized with a tumor targeting, cell penetrating peptide tLyp1 (CGNKRTR) was developed to co-encapsulate doxorubicin (DOX, ICD inducer) and 1MT (IDO inhibitor). The functionalized transfersomes were complexed with microneedles (MNs) to realize co-delivery towards primary tumors and TDLNs via transdermal administration. The transfersomes were concentrated in the needles of MNs and released with needle dissolution after insertion into skin. After being internalized by cells, DOX induced tumor ICD effect to promote DCs maturation and dramatically activated cytotoxic T lymphocytes (CD8+ T), while 1MT inhibited IDO activity in DCs and reduced the immunosuppressive Tregs, thus mitigating tumor suppressive microenvironment. The nano-complexed microneedles exhibited 2.2-fold suppression in tumor growth compared with the I.V. group, which significantly enhanced anti-tumor effect. [Display omitted] [ABSTRACT FROM AUTHOR]