Nanomedicine: Nanotechnology, Biology and Medicine最新文献

Combination chemotherapy with systemic administration of drugs in their free form can be challenging due to non-synchronized pharmacokinetics and sub-optimal tumor accumulation. The present study investigates a PLA-based block copolymeric nanocarrier for the co-delivery of navitoclax and decitabine (NAV/DCB NPs) for combination cancer therapy. NAV/DCB NPs exhibited potent in vitro synergistic cytotoxicity in both acute myeloid leukemia and breast cancer cell lines. Biodistribution studies of NAV/DCB NPs in tumor bearing mice, showed significant drug accumulation in tumor tissue and detectable quantities in plasma even after 48 h. Good hemocompatibility with reduced in vivo platelet toxicity indicated that encapsulation in PLA-based nanocarrier helped ameliorate navitoclax associated thrombocytopenia. In vivo biological activity of NAV/DCB NPs evaluated in xenograft AML and syngeneic breast cancer model, demonstrated potent tumor growth inhibition efficacy. PLA-based NAV/DCB dual NPs present a novel, safe and effective nanoformulation for combination cancer therapy in both solid tumors and hematologic malignancies.

Cervical diseases such as lymph node disease and tubal obstruction have threatened women's health. However, the traditional diagnostic methods still have shortcomings. NIR-II fluorescence imaging with advantages of low scattering, negligible autofluorescence, and high spatial resolution could be an ideal option. To obtain high quality NIR-II fluorescence imaging, selecting appropriate nanoprobes becomes the important issue. As a small molecular photothermal agent, extensive applications of ICG are rather limited because of its drawbacks. Herein, natural silk fibroin (SF) was synthesized and encapsulated ICG molecules to form SF@ICG nanoparticles (NPs). After detailed analysis, SF@ICG NPs showed excellent stability and long circulation time, as well as strong NIR-II fluorescence emission, well photo-stability, biocompatibility and well photothermal property under 808 nm laser irradiation. Furthermore, SF@ICG NPs were utilized for NIR-II fluorescence imaging of lymph node/lymphangiography and angiography of fallopian tubes. The process of fallopian tubes could be detected with high resolution and high sensitivity.

In a context of drug repurposing, pentamidine (PTM), an FDA-approved antiparasitic drug, has been proposed to reverse the splicing defects associated in myotonic dystrophy type 1 (DM1). However, clinical use of PTM is hinder by substantial toxicity, leading to find alternative delivery strategies. In this work we proposed hyaluronic acid-based nanoparticles as a novel encapsulation strategy to efficiently deliver PTM to skeletal muscles cells. In vitro studies on C2C12 myoblasts and myotubes showed an efficient nanoparticles' internalization with minimal toxicity. More interestingly, our findings evidenced for the first time the endosomal escape of hyaluronic acid-based nanocarriers. Ex vivo studies showed an efficient nanoparticles' internalization within skeletal muscle fibers. Finally, the therapeutic efficacy of PTM-loaded nanosystems to reduce the number of nuclear foci has been demonstrated in a novel DM1 in vitro model. So far, current data demonstrated the potency of hyaluronic acid-based nanosystems as efficient nanocarrier for delivering PTM into skeletal muscle and mitigate DM1 pathology.

The delivery of therapeutics across the cell membrane and into the cytoplasm is a major challenge that limits the development of new therapies. This challenge is compounded by the lack of a general assay for cytosolic delivery. Here we develop this assay based on the pro-fluorophore CrAsH-EDT2, and provide cytosolic penetration results for a variety of drug delivery agents (polyethyleneimine, poly-arginine, Ferritin, poly [maleic anhydride-alt-isobutene] grafted with dodecylamine, and cationic liposomes) into HeLa and T98G cells. Our results show that this method can be widely applicable to different cells and drug delivery agents, and yield statistically robust results. We later use this method to optimize and improve a model drug delivery agent's (Ferritin) cytosolic penetration.

Extracellular vesicles (EVs), nanovesicles released by cells to effectively exchange biological information, are gaining interest as drug delivery system. Yet, analogously to liposomes, they show short blood circulation times and accumulation in the liver and the spleen. For tissue specific delivery, EV surfaces will thus have to be functionalized. We present a novel platform for flexible modification of EVs with target-specific ligands based on the avidin-biotin system. Genetic engineering of donor cells with a glycosylphosphatidylinositol-anchored avidin (GPI-Av) construct allows the isolation of EVs displaying avidin on their surface, functionalized with any biotinylated ligand. For proof of concept, GPI-Av EVs were modified with i) a biotinylated antibody or ii) de novo designed and synthesized biotinylated ligands binding carbonic anhydrase IX (CAIX), a membrane associated enzyme overexpressed in cancer. Functionalized EVs showed specific binding and uptake by CAIX-expressing cells, demonstrating the power of the system to prepare EVs for cell-specific drug delivery.

In addition to exhibited antioxidant and anti-inflammatory activity, fullerene C60 is a promising wound healing agent. An important stage in the production of fullerene-based ointments is the stability of the aqueous fullerene dispersion (AFD) with minimum size of colloidal fullerene aggregates and sufficiently high concentration. To achieve these parameters tangential flow filtration of fullerene C60 was used (“green technology”).

As estimated by small-angle neutron scattering and dynamic light scattering purified AFDs with narrow-size distribution nanoclusters have a size of 6 nm and are assembled into agglomerates which reach a size of 150 nm.

The ability of the AFD to exhibit regenerative activity was studied using the animal wound model. This study shows for the first time that the fullerene-based composition stimulates the healing of wounds of various origins. We assume that the mechanism of the AFD wound-healing activity is associated with the aryl hydrocarbon receptor and macrophages activity.

Spinal cord injury (SCI) is a severe traumatic disease because of its complications and multi-organ dysfunction. After the injury, the disruption of microenvironment homeostasis in the lesion demolishes the surrounding healthy tissues via various pathways. The microenvironment regulation is beneficial for neural and functional recovery. Sustained release, cellular uptake, and long-term retention of therapeutic molecules at the impaired sites are important for continuous microenvironment improvement. In our study, a local-implantation system was constructed for SCI treatment by encapsulating exosomes derived from Flos Sophorae Immaturus (so-exos) in a polydopamine-modified hydrogel (pDA-Gel). So-exos are used as nanoscale natural vehicles of rutin, a flavonoid phytochemical that is effective in microenvironment improvement and nerve regeneration. Our study showed that the pDA-Gel-encapsulated so-exos allowed rapid improvement of the impaired motor function and alleviation of urination dysfunction by modulating the spinal inflammatory and oxidative conditions, thus illustrating a potential SCI treatment through a combinational delivery of so-exos.

Drug development for multiple sclerosis (MS) clinical management focuses on both neuroprotection and repair strategies, and is challenging due to low permeability of the blood-brain barrier, off-target distribution, and the need for high doses of drugs. The changes in the extracellular matrix have been documented in MS patients. It has been shown that the expression of nidogen-1 increases in MS lesions. Laminin forms a stable complex with nidogen-1 through a heptapeptide which was selected to target the lesion area in this study. Here we showed that the peptide binding was specific to the injured area following lysophosphatidylcholine (LPC) induced demyelination. In vivo data showed enhanced delivery of the peptide-functionalized gold nanoparticles (Pep-GNPs) to the lesion area. In addition, Pep-GNPs administration significantly enhanced myelin content and reduced astrocyte/microglia activation. Results demonstrated the possibility of using this peptide to target and treat lesions in patients suffering from MS.

PASylation, which was recently reported as the conjugation of pharmacologically active compounds with polypeptide sequences mainly made of proline, alanine and serine, has been proposed as an alternative to PEGylation. In this study, we designed PAS-modified liposomes (PASylated liposomes) and studied the effect of the incorporation of PAS-lipid on the stability and pharmacokinetic properties of liposomes, and compared them both in vitro and in vivo to PEGylated liposomes. Results showed that PASylated liposomes modified with single-chained PAS-lipid C₁₆-(PA₃)₇ (SC-PAS-Lip) showed comparable storage and serum stability to PEGylated liposomes (PEG-Lip), and a significantly decreased macrophage uptake compared with unmodified liposomes. SC-PAS-Lip displayed long circulating pharmacokinetic profile which was not impacted by the repeated administration of liposomes, and they were less likely to induce the production of anti-PEG IgM compared with PEGylated liposomes, presenting PASylation as an alternative liposome modification strategy to PEGylation.

Copper diethyldithiocarbamate [Cu(DDC)₂] is a promising anticancer agent. However, its poor water solubility is a significant obstacle to clinical application. In previous studies, we developed a stabilized metal ion ligand complex (SMILE) method to prepare Cu(DDC)₂ nanoparticle (NP) to address the drug delivery challenge. In the current study, we investigate the use of Cu(DDC)₂ NP for treating P-glycoprotein (P-gp) mediated drug-resistant cancers. We tested its anticancer efficacy with extensive in vitro cell-based assays and in vivo xenograft tumor model. We also explored the mechanism of overcoming drug resistance by Cu(DDC)₂ NP. Our results indicate that Cu(DDC)₂ NP is not a substrate of P-gp and thus can avoid P-gp mediated drug efflux. Further, the Cu(DDC)₂ NP does not inhibit the activity or the expression of P-gp.