Iron-Doxorubicin Hyaluronan Nanogel as an Effective Targeted Chemotherapy with Modulated Cardiotoxicity.

The complex of doxorubicin (Dox) and intracellular iron in cardiomyocytes generates reactive oxygen species (ROS), contributing to commonly observed cardiotoxicity. To enhance the anticancer potency and minimize the cardiotoxicity, here Dox was formulated into a hyaluronan (HA) nanogel using ferric ion (Fe) coordination to control the intracellular distribution and release of Dox. Taking advantage of the paramagnetic properties of iron and the fluorescence of Dox, we conveniently monitored the targeted delivery of the HA@Dox nanogel in murine breast tumors through both T1-weighted magnetic resonance imaging and fluorescence imaging.

Hijacking the hyaluronan assisted iron endocytosis to promote the ferroptosis in anticancer photodynamic therapy.

Photodynamic therapy (PDT) eradicates tumor cells by the light-stimulated reactive oxygen species, which also induces lipid peroxidation (LPO) and subsequently ferroptosis, an iron-depended cell death. Ferroptosis has a tremendous therapeutic potential in cancer treatment, however, the ferroptosis efficiency is largely limited by the available iron in cells. Through hijacking the CD44-mediated iron endocytosis of hyaluronan (HA), here PDT with enhanced ferroptosis was realized by a HA@Ce6 nanogel self-assembled from HA, a photosensitizer Chlorin e6 (Ce6) and Fe as cross-linkers.

senescence imaging nanoprobe targets the associated reactive oxygen species.

Cellular senescence, a cell-cycle arrest state upon stress or damage, can adversely impact aging and cancers. We have designed a novel near infrared fluorogenic nanoprobe, named D3, which can only be turned on by highly elevated levels of reactive oxygen species (ROS), critical players for the induction and maintenance of senescence, for real-time senescence sensing and imaging. In contrast to glowing senescent cells, non-senescent cells whose ROS levels are too low to activate the D3 signal remain optically silent.

Aptamer-Gemcitabine Conjugates with Enzymatically Cleavable Linker for Targeted Delivery and Intracellular Drug Release in Cancer Cells.

Gemcitabine is a chemotherapeutic used clinically to treat a variety of cancers. However, because it lacks tumor cell specificity, gemcitabine may cause off-target cytotoxicity and adversely impact patients. To impart cancer cell specificity to gemcitabine and improve its therapeutic efficacy, we synthesized a unique aptamer-drug conjugate that carries a high gemcitabine payload (three molecules) via a dendrimer structure and enzymatically cleavable linkers for controlled intracellular drug release.

Developing a far-red fluorogenic beta-galactosidase probe for senescent cell imaging and photoablation.

A methylene blue (MB)-based beta-galactosidase (β-gal) activatable molecule, Gal-MB, was developed for senescence imaging and light-triggered senolysis. When in contact with β-gal or senescence-associated β-gal (SA-β-gal), the photoinsensitive Gal-MB becomes fluorescent. Gal-MB also offered selective phototoxicity toward β-gal expressing cells and drug-induced senescent cells, which express SA-β-gal, after light illumination at 665 nm.

RHAMM-mediated bifunctional nanotherapy targeting Bcl-xL and mitochondria for pancreatic neuroendocrine tumor treatment.

The incidence of pancreatic neuroendocrine tumor (PNET) has continued to rise. Due to their indolent feature, PNET patients often present with incurable, metastatic diseases. Novel therapies are urgently needed.

A Hybrid Nanogel to Preserve Lysosome Integrity for Fluorescence Imaging.

Fluorescence imaging of lysosomes provides a powerful tool to probe the lysosome physiology in living cells, yet the continuous light exposure inevitably causes lysosome damage and phototoxicity, which remains a formidable challenge. Here the long-term lysosome tracking with minimized photodamage was realized using a multifunctional nanoprobe, a platinum nanoparticle, and a quinacrine co-loaded nanogel. To construct the hybrid nanogel, cisplatin first functioned as cross-linker to withhold all components and then was reduced to a platinum nanoparticle by ethanol.

Near-Infrared Fluorogenic Spray for Rapid Tumor Sensing.

Surgical resection of cancerous tissues is a critical procedure for solid tumor treatment. During the operation, the surgeon mostly identifies the cancerous tissues by naked-eye visualization under white light without aid, therefore, the outcome heavily relies on the surgeon's experience. A near-infrared pH-responsive fluorogenic dye, CypH-11, was designed to be used as a sensitive cancer spray to highlight cancerous tissues during surgical operations, minimizing the surgeon's subjective judgment.

Enzyme-Assisted Photodynamic Therapy Based on Nanomaterials.

Photodynamic therapy (PDT) is a noninvasive cancer treatment that requires the copresence of a photosensitizer (PS), oxygen, and light. The efficacy of conventional PDT is usually limited by two factors: delivery of the PS to the tumor and the hypoxic solid tumor environment. To improve the efficacy of PDT, nanomaterial-based, enzyme-assisted PDT (nano-ezPDT), which integrates enzyme-responsive components into nanomedicines, was developed for enhanced PS delivery and oxygen generation.

Selective photo-ablation of glioma cells using an enzyme activatable photosensitizer.

An activatable photosensitizer based on methylene blue was developed and validated for its efficacy in the selective killing of γ-glutamyl transpeptidase expressing cells. The O deactivation via bond breakage, rapid in situ enzymatic photosensitivity conversion, long lysosomal retention, and nucleus relocation collectively contribute to its strong and selective photodynamic effects.

A combined approach of convection-enhanced delivery of peptide nanofiber reservoir to prolong local DM1 retention for diffuse intrinsic pontine glioma treatment.

Background: Diffuse intrinsic pontine glioma (DIPG) is a highly lethal malignancy that occurs predominantly in children. DIPG is inoperable and post-diagnosis survival is less than 1 year, as conventional chemotherapy is ineffective. The intact blood-brain barrier (BBB) blocks drugs from entering the brain.

Aptamer-Equipped Protamine Nanomedicine for Precision Lymphoma Therapy.

Anaplastic large cell lymphoma (ALCL) is the most common T-cell lymphoma in children. ALCL cells characteristically express surface CD30 molecules and carry the pathogenic ALK oncogene, both of which are diagnostic biomarkers and are also potential therapeutic targets. For precision therapy, we report herein a protamine nanomedicine incorporated with oligonucleotide aptamers to selectively target lymphoma cells, a dsDNA/drug payload to efficiently kill targeted cells, and an siRNA to specifically silence ALK oncogenes.

Multifunctional Nanodelivery Platform for Maximizing Nucleic Acids Combination Therapy.

The silencing of an oncogene with a small interfering RNA (siRNA) is a promising way for cancer therapy. Its efficacy can be further enhanced by integrating with other therapeutics; however, transporting siRNA and other active ingredients to the same location at the same time is challenging. Here, we report a novel multifunctional nanodelivery platform by sequentially layering several functional ingredients, such as siRNAs, microRNAs, peptides, and targeting ligands, onto a core through charge-charge interaction.

Multilayered Activatable Nanoprobe for Ultra-Bright Tumor Imaging.

The development of tumor targeted probes with strong signal and high contrast is always challenging in cancer imaging. Here, a unique multilayered activatable nanoprobe (MAN) is prepared to fulfill this long-standing goal. MAN adopts a versatile layer-by-layer fabrication technique that sequentially assembles multifunctional polyelectrolytes onto nanoparticles via charge-charge interaction.

A Multiresponsive Nanohybrid to Enhance the Lysosomal Delivery of Oxygen and Photosensitizers.

Photodynamic therapy (PDT) is a promising cancer ablation method, but its efficiency is easily affected by several factors, such as the insufficient delivery of photosensitizers, low oxygen levels as well as long distance between singlet oxygen and intended organelles. A multifunctional nanohybrid, named MGAB, consisting of gelatin-coated manganese dioxide and albumin-coated gold nanoclusters, was designed to overcome these issues by improving chlorin e6 (Ce6) delivery and stimulating oxygen production in lysosomes. MGAB were quickly degraded in a high hydrogen peroxide, high protease activity, and low pH microenvironment, which is closely associated with tumor growth.

Layer-by-layer construction of an oxygen-generating photo-responsive nanomedicine for enhanced photothermal and photodynamic combination therapy.

A multifunctional photosensitive and photothermal nanomedicine, AMP-Ce6-HA, was prepared by sequentially layering hard and soft functional molecules. AMP-Ce6-HA was efficiently picked up by MDA-MB-231 breast cancer cells, and then released oxygen in lysosomes. The photothermal and oxygen-enhanced photodynamic combination therapy was much more effective than the single one.

Nanoparticle Delivery of miR-708 Mimetic Impairs Breast Cancer Metastasis.

Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course, higher rate of recurrence, and a conspicuous lack of FDA-approved targeted therapies. Here, we show that multilayered nanoparticles (NPs) carrying the metastasis suppressor microRNA miR-708 (miR708-NP) localize to orthotopic primary TNBC, and efficiently deliver the miR-708 cargo to reduce lung metastasis. Using a SOX2/OCT4 promoter reporter, we identified a population of miR-708 cancer cells with tumor-initiating properties, enhanced metastatic potential, and marked sensitivity to miR-708 treatment.

Redox-responsive cisplatin nanogels for anticancer drug delivery.

Inspired by cisplatin's deactivation by glutathione (GSH) in cancer, a GSH responsive nanogel loaded with doxorubicin (Dox) was prepared using hyaluronan as a matrix and cisplatin as a crosslinker. The elevated GSH depletes the cisplatin crosslinker in the nanogel, enhances Dox release and boosts cytotoxicity, thus providing a new GSH responsive platform to reverse cisplatin resistance.

Facile metabolic glycan labeling strategy for exosome tracking.

Background: Exosomes are nano-sized vesicles derived from the fusion of multivesicular bodies with the surrounding plasma membrane. Exosomes have various diagnostic and therapeutic potentials in cancer and other diseases, thus tracking exosomes is an important issue.

Methods: Here, we report a facile exosome labeling strategy using a natural metabolic incorporation of an azido-sugar into the glycan, and a strain-promoted azide-alkyne click reaction.

Lysosome Enlargement Enhanced Photochemotherapy Using a Multifunctional Nanogel.

Large lysosomes are susceptible toward rupture because of an increased membrane tension. Here we report a strategy to first enlarge and weaken the lysosome and then destroy it to boost the efficiency of photochemotherapy using a hyaluronan nanogel, carrying chloroquine as a lysosomal expander, rhodamine B as a photosensitive lysosomal destroyer, and cisplatin as a chemotherapeutic. This all-in-one nanogel provides a facile approach and new insight into improve the photochemotherapy, by making use of lysosome's size, as a risk factor in lysosomal destabilization.

Real-Time Visualization of Lysosome Destruction Using a Photosensitive Toluidine Blue Nanogel.

Breaking the lysosome helps its sequestered payloads access their molecular targets in cells and thus enhances the intracellular drug delivery. Current strategies for lysosomal escape involve direct physical interactions with the lipid membrane. These interactions pose a systemic toxicity and uncontrolled membrane rupture risk.

A cell surface clicked navigation system to direct specific bone targeting.

Cell therapies are promising up-and-coming therapeutic strategies for many diseases. For maximal therapeutic benefits, injected cells have to navigate their way to a designated area, including organ and tissue; unfortunately, the majority of therapeutic cells are currently administered without a guide or homing device. To improve this serious shortcoming, a functionalization method was developed to equip cells with a homing signal.

Sequence-Independent DNA Nanogel as a Potential Drug Carrier.

DNA nanostructures largely rely on pairing DNA bases; thus, sequence designing is required. Here, this study demonstrates a sequence-independent strategy to fabricate DNA nanogel (NG) inspired by cisplatin, a chemotherapeutic drug that acts as a DNA crosslinker. A simple heating and cooling of the genomic DNA extracts and cisplatin produces DNA NG with a size controlled by the heating time.

Volume of distribution and clearance of peptide-based nanofiber after convection-enhanced delivery.

OBJECTIVE Drug clearance may be a limiting factor in the clinical application of convection-enhanced delivery (CED). Peptide-based nanofibers (NFPs) have a high aspect ratio, and NFPs loaded with drugs could potentially maintain effective drug concentrations for an extended period sufficient for cancer therapy. The objective of this study was to assess the volume of distribution (Vd) and clearance of variable lengths of NFPs when administered using CED.

Total control of fat cells from adipogenesis to apoptosis using a xanthene analog.

Overcrowded adipocytes secrete excess adipokines and cytokines under stress, which results in a deregulated metabolism. This negative response to stress increases the possibility of obesity and several of its associated diseases, such as cancer and atherosclerosis. Therefore, a reduction in the number of adipocytes may be a rational strategy to relieve the undesired expansion of adipose tissue.