pH-responsive targeted nanoparticles release ERK-inhibitor in the hypoxic zone and sensitize free gemcitabine in mutant K-Ras-addicted pancreatic cancer cells and mouse model.

Therapeutic options for managing Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest types of aggressive malignancies, are limited and disappointing. Therefore, despite suboptimal clinical effects, gemcitabine (GEM) remains the first-line chemotherapeutic drug in the clinic for PDAC treatment. The therapeutic limitations of GEM are primarily due to poor bioavailability and the development of chemoresistance resulting from the addiction of mutant-K-RAS/AKT/ERK signaling-mediated desmoplastic barriers with a hypoxic microenvironment. Several new therapeutic approaches, including nanoparticle-assisted drug delivery, are being investigated by us and others. This study used pH-responsive nanoparticles encapsulated ERK inhibitor (SCH772984) and surface functionalized with tumor-penetrating peptide, iRGD, to target PDAC tumors. We used a small molecule, SCH772984, to target ERK1 and ERK2 in PDAC and other cancer cells. This nanocarrier efficiently released ERKi in hypoxic and low-pH environments. We also found that the free-GEM, which is functionally weak when combined with nanoencapsulated ERKi, led to significant synergistic treatment outcomes in vitro and in vivo. In particular, the combination approaches significantly enhanced the GEM effect in PDAC growth inhibition and prolonged survival of the animals in a genetically engineered KPC (LSL-KrasG12D/+/LSL-Trp53R172H/+/Pdx-1-Cre) pancreatic cancer mouse model, which is not observed in a single therapy. Mechanistically, we anticipate that the GEM efficacy was increased as ERKi blocks desmoplasia by impairing the production of desmoplastic regulatory factors in PDAC cells and KPC mouse tumors. Therefore, 2nd generation ERKi (SCH 772984)-iRGD-pHNPs are vital for the cellular response to GEM and denote a promising therapeutic target in PDAC with mutant K-RAS.

Bioinspired Materials for Wearable Devices and Point-of-Care Testing of Cancer.

Wearable, point-of-care diagnostics, and biosensors are on the verge of bringing transformative changes in detection, management, and treatment of cancer. Bioinspired materials with new forms and functions have frequently been used, in both translational and commercial spaces, to fabricate such diagnostic platforms. Engineered from organic or inorganic molecules, bioinspired systems are naturally equipped with biorecognition and stimuli-sensitive properties. Mechanisms of action of bioinspired materials are deeply connected with thermodynamically or kinetically controlled self-assembly at the molecular and supramolecular levels. Thus, integration of bioinspired materials into wearable devices, either as triggers or sensors, brings about unique device properties usable for detection, capture, or rapid readout for an analyte of interest. In this review, we present the basic principles and mechanisms of action of diagnostic devices engineered from bioinspired materials, describe current advances, and discuss future trends of the field, particularly in the context of cancer.

Polymeric Composite Matrix with High Biobased Content as Pharmaceutically Relevant Molecular Encapsulation and Release Platform.

Drug delivery systems (DDS) that can temporally control the rate and extent of release of therapeutically active molecules find applications in many clinical settings, ranging from infection control to cancer therapy. With an aim to design a locally implantable, controlled-release DDS, we demonstrated the feasibility of using cellulose nanocrystal (CNC)-reinforced poly (l-lactic acid) (PLA) composite beads. The performance of the platform was evaluated using doxorubicin (DOX) as a model drug for applications in triple-negative breast cancer. A facile, nonsolvent-induced phase separation (NIPS) method was adopted to form composite beads. We observed that CNC loading within these beads played a critical role in the mechanical stability, porosity, water uptake, diffusion, release, and pharmacological activity of the drug from the delivery system. When loaded with DOX, composite beads significantly controlled the release of the drug in a pH-dependent pattern. For example, PLA/CNC beads containing 37.5 wt % of CNCs showed a biphasic release of DOX, where 41 and 82% of the loaded drug were released at pH 7.4 and pH 5.5, respectively, over 7 days. Drug release followed Korsmeyer's kinetics, indicating that the release mechanism was mostly diffusion and swelling-controlled. We showed that DOX released from drug-loaded PLA/CNC composite beads locally suppressed the growth and proliferation of triple-negative breast cancer cells, MBA-MB-231, via the apoptotic pathway. The efficacy of the DDS was evaluated in human tissue explants. We envision that such systems will find applications for designing biobased platforms with programmed stability and drug delivery functions.

Author Correction: Cellulose Mediated Transferrin Nanocages for Enumeration of Circulating Tumor Cells for Head and Neck Cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Cellulose Mediated Transferrin Nanocages for Enumeration of Circulating Tumor Cells for Head and Neck Cancer.

Herein we report a hierarchically organized, water-dispersible 'nanocage' composed of cellulose nanocrystals (CNCs), which are magnetically powered by iron oxide (Fe3O4) nanoparticles (NPs) to capture circulating tumor cells (CTCs) in blood for head and neck cancer (HNC) patients. Capturing CTCs from peripheral blood is extremely challenging due to their low abundance and its account is clinically validated in progression-free survival of patients with HNC. Engaging multiple hydroxyl groups along the molecular backbone of CNC, we co-ordinated Fe3O4 NPs onto CNC scaffold, which was further modified by conjugation with a protein - transferrin (Tf) for targeted capture of CTCs. Owing to the presence of Fe3O4 nanoparticles, these nanocages were magnetic in nature, and CTCs could be captured under the influence of a magnetic field. Tf-CNC-based nanocages were evaluated using HNC patients' blood sample and compared for the CTC capturing efficiency with clinically relevant Oncoviu platform. Conclusively, we observed that CNC-derived nanocages efficiently isolated CTCs from patient's blood at 85% of cell capture efficiency to that of the standard platform. Capture efficiency was found to vary with the concentration of Tf and Fe3O4 nanoparticles immobilized onto the CNC scaffold. We envision that, Tf-CNC platform has immense connotation in 'liquid biopsy' for isolation and enumeration of CTCs for early detection of metastasis in cancer.