Anti-VEGF PolysiRNA Polyplex for the Treatment of Choroidal Neovascularization.

Choroidal neovascularization (CNV) is a major cause of severe vision loss in patients with age-related macular degeneration (AMD). Present ocular siRNA delivery technology is limited due to poor delivery through the retina to the choroid, where CNV originates. Our goal was to develop an optimized nanosized polyRNAi-based therapeutic delivery system to the subretinal space. We developed it by siRNA multimerization (polysiRNA) followed by coating with branched polyethylenimine and hyaluronic acid, and then evaluated its efficacy in vitro and in vivo. The polysiRNA polyplex showed a narrow size distribution (260.7 ± 43.27 nm) and negative charge (-4.98 ± 0.47 mV) owing to the hyaluronic acid outer layer. In vitro uptake of the polysiRNA polyplex by human ARPE cells was discovered, and the direct inhibition of VEGF mRNA translation was confirmed in B16F10 cells. The intravitreally administered polysiRNA polyplex overcame both the vitreous and retina barriers in vivo and reached the subretinal space efficiently. Intravitreal injection of the polysiRNA polyplex was not toxic to the retina in histopathology. Furthermore, intravitreal injections of the polysiRNA polyplex at both 1 and 7 days after laser photocoagulation inhibited laser-induced choroidal neovascularization, compared to that of the control (p < 0.05). These results suggest that anti-VEGF polysiRNA polyplexes show great potential in delivering multimeric RNAi-based therapeutics to treat retinal or choroidal disorders.

Multifunctional theranostic contrast agent for photoacoustics- and ultrasound-based tumor diagnosis and ultrasound-stimulated local tumor therapy.

Biomedical imaging-guided cancer therapy should have capabilities of both accurate tumor diagnosis and high therapeutic efficacy for the personalized treatment. Various biomedical imaging-guided cancer therapies are currently being investigated to overcome current limitations that include low sensitivity of diagnosis and poor drug delivery to the tumor site. Here, we report the development of a multifunctional theranostic contrast agent demonstrating high sensitive photoacoustic and ultrasound imaging and effective local delivery of anticancer drug to a tumor site. A microbubble (porphyrin-MB) was developed using phospholipid-porphyrin conjugates to enhance ultrasound and photoacoustic signal intensities simultaneously. Paclitaxel-loaded human serum albumin nanoparticles (PTX-HSA-NPs) were then conjugated onto the surface of the microbubble. The developed PTX-HSA-NPs conjugated porphyrin-MB (porphyrin-MB-NPs) provided sensitive, dual modal images of a tumor at 700 nm optimal laser wavelength for photoacoustic imaging and 5-14 MHz operating frequency for the ultrasound imaging. In addition, porphyrin-MB-NPs efficiently suppressed tumor growth by ultrasound exposure. Exposure to the focused ultrasound triggered the collapse of porphyrin-MB-NPs, resulting in the local release of PTX-HSA-NPs and enhanced penetration into the tumor site. The increased preferential accumulation and penetration of PTX-HSA-NPs suppressed tumor growth 10-fold more than without exposure to ultrasound. In conclusion, the developed porphyrin-MB-NPs establish a new paradigm in simultaneous bi-functional ultrasound/photoacoustic imaging diagnosis and locally triggered release of nanomedicine and enhanced chemotherapy efficiency.

Amplified photoacoustic performance and enhanced photothermal stability of reduced graphene oxide coated gold nanorods for sensitive photoacoustic imaging.

We report a strongly amplified photoacoustic (PA) performance of the new functional hybrid material composed of reduced graphene oxide and gold nanorods. Due to the excellent NIR light absorption properties of the reduced graphene oxide coated gold nanorods (r-GO-AuNRs) and highly efficient heat transfer process through the reduced graphene oxide layer, r-GO-AuNRs exhibit excellent photothermal stability and significantly higher photoacoustic amplitudes than those of bare-AuNRs, nonreduced graphene oxide coated AuNRs (GO-AuNRs), or silica-coated AuNR, as demonstrated in both in vitro and in vivo systems. The linear response of PA amplitude from reduced state controlled GO on AuNR indicates the critical role of GO for a strong photothermal effect of r-GO-AuNRs. Theoretical studies with finite-element-method lab-based simulation reveal that a 4 times higher magnitude of the enhanced electromagnetic field around r-GO-AuNRs can be generated compared with bare AuNRs or GO-AuNRs. Furthermore, the r-GO-AuNRs are expected to be a promising deep-tissue imaging probe because of extraordinarily high PA amplitudes in the 4-11 MHz operating frequency of an ultrasound transducer. Therefore, the r-GO-AuNRs can be a useful imaging probe for highly sensitive photoacoustic images and NIR sensitive therapeutics based on a strong photothermal effect.

Photoacoustic-based nanomedicine for cancer diagnosis and therapy.

Photoacoustic imaging is the latest promising diagnostic modality that has various advantages such as high spatial resolution, deep penetration depth, and use of non-ionizing radiation. It also employs a non-invasive imaging technique and optically functionalized imaging. The goal of this study was to develop a nanomedicine for simultaneous cancer therapy and diagnosis based on photoacoustic imaging. Human serum albumin nanoparticles loaded with melanin and paclitaxel (HMP-NPs) were developed using the desolvation technique. The photoacoustic-based diagnostic and chemotherapeutic properties of HMP-NPs were evaluated through in vitro and in vivo experiments. The size and zeta potential of the HMP-NPs were found to be 192.8±21.11nm and -22.2±4.39mV, respectively. In in vitro experiments, HMP-NPs produced increased photoacoustic signal intensity because of the loaded melanin and decreased cellular viability because of the encapsulated paclitaxel, compared to the free human serum albumin nanoparticles (the control). In vivo experiments showed that the HMP-NPs efficiently accumulated inside the tumor, resulting in the enhanced photoacoustic signal intensity in the tumor site, compared to the normal tissues. The in vivo chemotherapy study demonstrated that HMP-NPs had the capability to treat cancer for an extended period. In conclusion, HMP-NPs were simultaneously capable of photoacoustic diagnostic and chemotherapy against cancer.