Real-Time Quantification of Cartilage Degeneration by GAG-Targeted Cationic Nanoparticles for Efficient Therapeutic Monitoring in Living Mice.

One of the characterizations of degenerative cartilage disease is the progressive loss of glycosaminoglycans (GAGs). The real-time imaging method to quantify GAGs is of great significance for the biochemical analysis of cartilage and diagnosis and therapeutic monitoring of cartilage degeneration in vivo. To this end, a cationic photoacoustic (PA) contrast agent, poly-l-lysine melanin nanoparticles (PLL-MNPs), specifically targeting anionic GAGs was developed in this study to investigate whether it can image cartilage degeneration. PLL-MNP assessed GAG depletion by Chondroitinase ABC in vitro rat cartilage and intact ex vivo mouse knee joint. A papain-induced cartilage degenerative mice model was used for in vivo photoacoustic imaging (PAI). Oral cartilage supplement glucosamine sulfate was intragastrically administered for mice cartilage repair and the therapeutic efficacy was monitored by PLL-MNP-enhanced PAI. Histologic findings were used to further confirm PAI results. In vitro results revealed that the PLL-MNPs not only had a high binding ability with GAGs but also sensitively monitored GAG content changes by PAI. The PA signal was gradually weakened along with the depletion of GAGs in cartilage. Particularly, PLL-MNPs depicted the cartilage structure and the distribution of GAGs was demonstrated in PA images in ex vivo joints. Compared with the normal joint, a lower signal intensity was detected from degenerative joint at 3 weeks after papain injection, suggesting an early diagnosis of cartilage lesion by PLL-MNPs. Importantly, this PA-enhanced nanoprobe was suitable for monitoring in vivo efficacy of glucosamine sulfate, which effectively blocked cartilage degradation in a high dose manner. In vivo imaging findings correlated well with histological examinations. PLL-MNPs provided sensitive visualization of cartilage degeneration and promising monitoring of therapeutic response in living subjects.

Nanomedicine - advantages for their use in rheumatoid arthritis theranostics.

Rheumatoid arthritis (RA) is an autoimmune disease accompanies with synovial inflammation and progressive bone destruction. Currently, anti-rheumatic drugs need high dose and frequent use for a long-term, which lead to serious side effect and low patient compliance. To overcome above problems and improve clinical efficacy, nano-technology with targeting ability, sustained release and so forth, has been proposed on RA treatment and already achieved success in RA animal models. In this review, authors summarize and illustrate representative nanomedicine targeting to RA states, which is achieved either through passive or active targeting with high affinity to the receptors that are over-expressed in macrophages or angiogenesis. In particular, authors highlight the new strategies to promote the efficacy of nanoscale treatments through phototherapy and the addition of contrast elements for theranostic application. The described advances may pave the way to better understanding and designing the novel nanomedicine and multifunctional nano-system on efficient RA treatment.

Gadolinium-Chelated Conjugated Polymer-Based Nanotheranostics for Photoacoustic/Magnetic Resonance/NIR-II Fluorescence Imaging-Guided Cancer Photothermal Therapy.

Our exploiting versatile multimodal theranostic agent aims to integrate the complementary superiorities of photoacoustic imaging (PAI), second near-infrared (NIR-II, 1000-1700) fluorescence and T1-weighted magnetic resonance imaging (MRI) with an ultimate objective of perfecting cancer diagnosis, thus improving cancer therapy efficacy. Herein, we engineered and prepared a water-soluble gadolinium-chelated conjugated polymer-based theranostic nanomedicine (PFTQ-PEG-Gd NPs) for in vivo tri-mode PA/MR/NIR-II imaging-guided tumor photothermal therapy (PTT). Methods: We firstly constructed a semiconducting polymer composed of low-bandgap donor-acceptor (D-A) which afforded the strong NIR absorption for PAI/PTT and long fluorescence emission to NIR-II region for in vivo imaging. Then, the remaining carboxyl groups of the polymeric NPs could effectively chelate with Gd3+ ions for MRI. The in vitro characteristics of the PFTQ-PEG-Gd NPs were studied and the in vivo multimode imaging as well as anti-tumor efficacy of the NPs was evaluated using 4T1 tumor-bearing mice. Results: The obtained theranostic agent showed excellent chemical and optical stability as well as low biotoxicity. After 24 h of systemic administration using PQTF-PEG-Gd NPs, the tumor sites of living mice exhibited obvious enhancement in PA, NIR-II fluorescence and positive MR signal intensities. Better still, a conspicuous tumor growth restraint was detected under NIR light irradiation after administration of PQTF-PEG-Gd NPs, indicating the efficient photothermal potency of the nano-agent. Conclusion: we triumphantly designed and synthesized a novel and omnipotent semiconducting polymer nanoparticles-based theranostic platform for PAI, NIR-II fluorescence imaging as well as positive MRI-guided tumor PTT in living mice. We expect that such a novel organic nano-platform manifests a great promise for high spatial resolution and deep penetration cancer theranostics.

Lysosome-Assisted Mitochondrial Targeting Nanoprobe Based on Dye-Modified Upconversion Nanophosphors for Ratiometric Imaging of Mitochondrial Hydrogen Sulfide.

Hydrogen sulfide (H2S) is a versatile modulator in mitochondria and involved in numerous diseases caused by mitochondrial dysfunction. Therefore, many efforts have been made to develop fluorescent probes for mitochondrial H2S detection. However, these cationic small molecule probes are inapplicable for in vivo imaging because of the shallow tissue penetration and poor biostability. Herein, a ratiometric upconversion luminescence nanoprobe with an acid-activated targeting strategy is developed for detecting and bioimaging of mitochondrial H2S. The merocyanine triphenylamine-merocyanine (TPAMC)-modified upconversion nanophosphors, acting as the targeting and response component, are encapsulated into a pH-sensitive husk, composed of 1,2-distearoyl- sn-glycero-3-phosphoethanolamine- N-[methoxy-(poly(ethylene glycol))-2000] (DSPE-PEG) and poly(l-histidine)- b-PEG, which improved the nanoprobe's stability during transport in vivo. Under lysosomal pH, the PEG shell is interrupted and the targeting sites are exposed to further attach to mitochondria. Taking advantage of the luminescence resonance energy transfer process between TPAMC and upconversion nanophosphors, the ratiometric detection of mitochondrial H2S can be achieved with high selectivity and sensitivity. Cellular testing reveals the precise targeting to mitochondria via a lysosome delivery process. Importantly, the nanoprobe can be used for monitoring mitochondrial H2S levels in living cells and colon cancer mouse models.