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The recent progress in photonic nanomaterials has contributed greatly to the development of photomedicines. However, the finite depth of light penetration is still a serious limitation, constraining their clinical applications. Here, we developed a poly(allylamine) (PAAm)-modified upconversion nanoparticle/hyaluronate–rose bengal (UCNP/PAAm/HA-RB) conjugate complex for photochemical bonding of deep tissue with near-infrared (NIR) light illumination. Compared to the conventional invasive treatment via suturing and stapling, the UCNP/PAAm/HA-RB conjugate complex could be noninvasively delivered into the deep tissue and accelerate the tissue bonding upon NIR light illumination. HA in the outer layer of the complex facilitated the penetration of RB into the collagen layer of the dermis. The NIR light triggered UCNP of NaYF4: Yb/Er (Y:Yb:Er = 78:20:2) in the complex to illuminate visible green light under the skin tissue. The activated RB in the HA-RB conjugate by the green light induced radical formation for ...

Light-absorbing nanoparticles for localized heat generation in tissues have various biomedical applications in diagnostic imaging, surgery, and therapies. Although numerous plasmonic and carbon-based nanoparticles with strong optical absorption have been developed, their clearance, potential cytotoxicity, and long-term safety issues remain unresolved. Here, we show that "generally regarded as safe (GRAS)" melanoidins prepared from glucose and amino acid offer a high light-to-heat conversion efficiency, biocompatibility, biodegradability, nonmutagenicity, and efficient renal clearance, as well as a low cost for synthesis. We exhibit a wide range of biomedical photonic applications of melanoidins, including in vivo photoacoustic mapping of sentinel lymph nodes, photoacoustic tracking of gastrointestinal tracts, photothermal cancer therapy, and photothermal lipolysis. The biodegradation rate and renal clearance of melanoidins are controllable by design. Our results confirm the feasibility of biodegradable melanoidins for various photonic applications to theranostic nanomedicines.

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 ca. 37.3 nm and a negative surface charge of ca. -12 mV. With a negligible cytotoxicity, AuCM/siRNA/PEI/HA complex showed an excellent target-specific gene silencing efficiency of ca. 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.

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 in vitro and in vivo 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 in vitro 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.

Rheumatoid arthritis (RA) is a chronic inflammatory immune disease causing the inflammation of synovial membrane and the articular cartilage destruction. In this work, hyaluronate-gold nanoparticle/Tocilizumab (HA-AuNP/TCZ) complex was prepared for the treatment of RA. AuNP was used as a drug carrier with antiangiogenic effect. TCZ is a humanized monoclonal antibody against the interleukin-6 (IL-6) receptor and used as an immunosuppressive drug by interfering IL-6 in the pathogenesis of RA. HA is known to have cartilage-protective and lubricant effects. HA was modified with cystamine via reductive amination, which was reduced with dithiothreitol (DTT) to prepare end-group thiolated HA (HA-SH). AuNP was chemically modified with HA-SH and physically modified with TCZ. The formation of HA-AuNP/TCZ complex was corroborated by UV-vis spectroscopy, dynamic light scattering (DLS), and transmission electron microscopy (TEM). The therapeutic effect of HA-AuNP/TCZ complex on RA was confirmed in collagen-induced arthritis (CIA) model mice by ELISA, histological, and Western blot analyses.

Melanoma skin cancer is one of the most dangerous skin cancers and the main cause of skin-cancer-related mortality. Hyaluronic acid (HA) has been used as an effective transdermal delivery carrier of chemical drugs and biopharmaceuticals. In this work, a nanographene oxide-HA conjugate (NGO-HA) was synthesized for photothermal ablation therapy of melanoma skin cancer using a near-infrared (NIR) laser. Confocal microscopy and ex vivo bioimaging clearly visualized the remarkable transdermal delivery of NGO-HA to tumor tissues in the skin of mice, which might be ascribed to highly expressed HA receptors and relatively leaky structures around tumor tissues, enabling the enhanced permeation and retention of nanoparticles. The NIR irradiation resulted in complete ablation of tumor tissues with no recurrence of tumorigenesis. The antitumor effect was confirmed by ELISA for caspase-3 activity and histological and immunohistochemical analyses with TUNEL assay for tumor apoptosis. Taken together, we could confirm the feasibility of transdermal NGO-HA for photothermal ablation therapy of melanoma skin cancers.