PLGA Nanoparticles Grafted with Hyaluronic Acid to Improve Site-Specificity and Drug Dose Delivery in Osteoarthritis Nanotherapy.

Nanoparticles (NPs) have a tremendous potential in medicinal applications, and recent studies have pushed the boundaries in nanotherapy, including in osteoarthritis treatments. The aim of this study was to develop new poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) surfaces decorated with hyaluronic acid (HA) to enhance targeted drug specificity to the osteoarthritic knee joint. HA was selected since it binds to specific receptors expressed in many cells, such as the cluster determinant 44 (CD44), a major receptor of chondrocytes, and because of its function in the synovial fluid (SF), such as maintenance of high fluid viscosity. The PLGA polymer was grafted to sodium hyaluronate using dimethoxy-PEG (PLGA-HA) and compared with control PLGA NPs (not grafted). NPs were characterized by 1H-NMR and IR spectroscopy. Then, near-infrared (NIR) dye and gold (20 nm) were encapsulated in the formulated NPs and used to access NPs' performance in in vitro, in vivo, and ex vivo experiments. To test the NPs' CD44 receptor specificity, an antibody assay was performed. All NPs presented a size in the range viable for cell-uptake, no cytotoxicity to chondrocytes was registered. Although all the NPs had a high capacity to be absorbed by the cells, PLGA-HA NPs showed significantly higher affinity towards the chondrocytic C28/I2 cell line. In conclusion, PLGA NPs grafted to sodium hyaluronate showed increased binding to cartilage cells and tissue and enhanced accumulation at the target site. Thus, this study presents a safe drug-delivery system with improved receptor specificity, which may represent an advantageous alternative to current nanotherapies.

A scintillating nanoplatform with upconversion function for the synergy of radiation and photodynamic therapies for deep tumors.

Collaborative therapy is regarded as an effective approach in increasing the therapeutic efficacy of cancer. In this work, we have proposed and validated the concept of upconversion lumienscence image guided synergy of photodynamic therapy (PDT) and radiotherapy (RT) for deep cancer, via a specially designed nanoplatform integrating near infrared (NIR) light activated luminescence upconversion and X-ray induced scintillation. Upon NIR light irradiation, the nanoplatform emits highly monochromatic red light solely for imaging the targeted cancer cells without triggering therapy; however, when the irradiation turns to a low dose of X-rays, scintillation will occur which induces effectively the PDT destroying the cancer cells together with X-ray induced RT. The novel theranostic nanoplatform is constructed in such a way that the interactions between the upconversion core and the outmost scintillating shell are blocked effectively by an inert layer between them. This structural design not only enables a nearly perfect excitation energy delivery (∼100% at a spectral overlapping wavelength of ∼540 nm) from the outermost scintellating layer to the surface-anchored photosensitizers and so a maximum yield of radical oxygen species, but also achieves a strong NIR induced upconversion luminescence for imaging. Since PDT and RT attack different parts of a cancer cell, this synergy is more effective in destroying cancer than a single therapy, resulting in the reduction of the X-ray irradiation dosage. As a proof of principle, the theranostic effect is validated by in vitro and in vivo experiments, exhibiting the great potential of this sort of nanoplatform in deep cancer treatment.

PLGA-Nanoparticles for Intracellular Delivery of the CRISPR-Complex to Elevate Fetal Globin Expression in Erythroid Cells.

Ex vivo gene editing of CD34+ hematopoietic stem and progenitor cells (HSPCs) offers great opportunities to develop new treatments for a number of malignant and non-malignant diseases. Efficient gene-editing in HSPCs has been achieved using electroporation and/or viral transduction to deliver the CRISPR-complex, but cellular toxicity is a drawback of currently used methods. Nanoparticle (NP)-based gene-editing strategies can further enhance the gene-editing potential of HSPCs and provide a delivery system for in vivo application. Here, we developed CRISPR/Cas9-PLGA-NPs efficiently encapsulating Cas9 protein, single gRNA and a fluorescent probe. The initial 'burst' of Cas9 and gRNA release was followed by a sustained release pattern. CRISPR/Cas9-PLGA-NPs were taken up and processed by human HSPCs, without inducing cellular cytotoxicity. Upon escape from the lysosomal compartment, CRISPR/Cas9-PLGA-NPs-mediated gene editing of the γ-globin gene locus resulted in elevated expression of fetal hemoglobin (HbF) in primary erythroid cells. The development of CRISPR/Cas9-PLGA-NPs provides an attractive tool for the delivery of the CRISPR components to target HSPCs, and could provide the basis for in vivo treatment of hemoglobinopathies and other genetic diseases.

Correction to: Ceramide and palmitic acid inhibit macrophage-mediated epithelial-mesenchymal transition in colorectal cancer.

The third and fifth author's affiliation was published incorrectly in the original article. Also, the Figure 5 and the Acknowledgement section was published incorrectly. The corrected affiliation, Figure 5 and the Acknowledgement section are provided in this correction.

Ceramide and palmitic acid inhibit macrophage-mediated epithelial-mesenchymal transition in colorectal cancer.

Accumulating evidence indicates that ceramide (Cer) and palmitic acid (PA) possess the ability to modulate switching of macrophage phenotypes and possess anti-tumorigenic effects; however, the underlying molecular mechanisms are largely unknown. The aim of the present study was to investigate whether Cer and PA could induce switching of macrophage polarization from the tumorigenic M2- towards the pro-inflammatory M1-phenotype, and whether this consequently altered the potential of colorectal cancer cells to undergo epithelial-mesenchymal transition (EMT), a hallmark of tumor progression. Our study showed that Cer- and PA-treated macrophages increased expression of the macrophage 1 (M1)-marker CD68 and secretion of IL-12 and attenuated expression of the macrophage 2 (M2)-marker CD163 and IL-10 secretion. Moreover, Cer and PA abolished M2 macrophage-induced EMT and migration of colorectal cancer cells. At the molecular level, this coincided with inhibition of SNAI1 and vimentin expression and upregulation of E-cadherin. Furthermore, Cer and PA attenuated expression levels of IL-10 in colorectal cancer cells co-cultured with M2 macrophages and downregulated STAT3 and NF-κB expression. For the first time, our findings suggest the presence of an IL-10-STAT3-NF-κB signaling axis in colorectal cancer cells co-cultured with M2 macrophages, mimicking the tumor microenvironment. Importantly, PA and Cer were powerful inhibitors of this signaling axis and, consequently, EMT of colorectal cancer cells. These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of lipids for future combination with drugs in the therapy of colorectal carcinoma.

Optical imaging and pH-awakening therapy of deep tissue cancer based on specific upconversion nanophotosensitizers.

Side effect is one of the main factors affecting the success of cancer therapies in clinic. Patients treated with photodynamic therapy (PDT) suffer mainly from the phototoxicity due to the relatively long time blood circulation of the tumor enrichment and they have also to be protected from background light for days after the treatment. Here we introduce a new design of nanophotosensitizers in which the luminescence upconversion nanoparticles loaded with photosensitizers are self-assembled into a nanoball with the aid of a specific pH-sensitive polymer layer containing overloaded photosensitizers and quenching molecules. This design makes the therapy function "off/on" possible, i.e. only imaging during the circulation of the nanoballs ascribing to the near-infrared (NIR) photon upconversion of the nanoballs and the pH-sensitive shell. Activation of PDT solely occurs once the nanoballs are taken up by the cancer cells due to the acidic microenvironment. This design prevents effectively the photodamage of the photosensitizers during enrichment and targeting process of tumor, as validated in vitro and in vivo, which enables imaging-guided PDT treatment of deep-seated tumor in a much more relax and comfortable way for patients. This patient-friendly nanomaterial construction strategy can also be extended to other therapies.