Stimulating brain recovery after stroke using theranostic albumin nanocarriers loaded with nerve growth factor in combination therapy

For many years, delivering drug molecules across the blood brain barrier has been a major challenge. The neuropeptide nerve growth factor is involved in the regulation of growth and differentiation of cholinergic neurons and holds great potential in the treatment of stroke. However, as with many other compounds, the biomolecule is not able to enter the central nervous system. In the present study, nerve growth factor and ultrasmall particles of iron oxide were co-encapsulated into a chemically crosslinked albumin nanocarrier matrix which was modified on the surface with apolipoprotein E. These biodegradable nanoparticles with a size of 212 ± 1 nm exhibited monodisperse size distribution and low toxicity. They delivered NGF through an artificial blood brain barrier and were able to induce neurite outgrowth in PC12 cells in vitro. In an animal model of stroke, the infarct size was significantly reduced compared to the vehicle control. The combination therapy of NGF and the small-molecular MEK inhibitor U0126 showed a slight but not significant difference compared to U0126 alone. However, further in vivo evidence suggests that successful delivery of the neuropeptide is possible as well as the synergism between those two treatments

Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer

Background: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. Results: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. Conclusions: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising

Small-Sized Co-Polymers for Targeted Delivery of Multiple Imaging and Therapeutic Agents

Research has increasingly focused on the delivery of high, often excessive amounts of drugs, neglecting negative aspects of the carrier’s physical preconditions and biocompatibility. Among them, little attention has been paid to “small but beautiful” design of vehicle and multiple cargo to achieve effortless targeted delivery into deep tissue. The design of small biopolymers for deep tissue targeted delivery of multiple imaging agents and therapeutics (mini-nano carriers) emphasizes linear flexible polymer platforms with a hydrodynamic diameter of 4 nm to 10 nm, geometrically favoring dynamic juxtaposition of ligands to host receptors, and economic drug content. Platforms of biodegradable, non-toxic poly(β-l-malic acid) of this size carrying multiple chemically bound, optionally nature-derived or synthetic affinity peptides and drugs for a variety of purposes are described in this review with specific examples. The size, shape, and multiple attachments to membrane sites accelerate vascular escape and fast blood clearance, as well as the increase in medical treatment and contrasts for tissue imaging. High affinity antibodies routinely considered for targeting, such as the brain through the blood–brain barrier (BBB), are replaced by moderate affinity binding peptides (vectors), which penetrate at high influxes not achievable by antibodies

Rapid Chromatic Detection of Bacteria by Use of a New Biomimetic Polymer Sensor

We present a new platform for visual and spectroscopic detection of bacteria. The detection scheme is based on the interaction of membrane-active compounds secreted by bacteria with agar-embedded nanoparticles comprising phospholipids and the chromatic polymer polydiacetylene (PDA). We demonstrate that PDA undergoes dramatic visible blue-to-red transformations together with an intense fluorescence emission that are induced by molecules released by multiplying bacteria. The chromatic transitions are easily identified by the naked eye and can also be recorded by conventional high-throughput screening instruments. Furthermore, the color and fluorescence changes generally occur in shorter times than the visual appearance of bacterial colonies on the agar. The chromatic technology is generic and simple, does not require identification a priori of specific bacterial recognition elements, and can be applied for detection of both gram-negative and gram-positive bacteria. We demonstrate applications of the new platform for reporting on bacterial contaminations in foods and for screening for bacterial antibiotic resistance

Maghemite-containing PLGA–PEG-based polymeric nanoparticles for siRNA delivery: toxicity and silencing evaluation

Gene therapy based on siRNA has emerged as an exciting new therapeutic approach. In this work, incorporation of PEI into PLGA-b-PEG and encapsulation of magnetic NPs as MRI contrast agent, resulted in unique theranostic nanoparticles

Covalent nano delivery systems for selective imaging and treatment of brain tumors.

Nanomedicine is a rapidly evolving form of therapy that holds a great promise for superior drug delivery efficiency and therapeutic efficacy than conventional cancer treatment. In this review, we attempt to cover the benefits and the limitations of current nanomedicines with special attention to covalent nano conjugates for imaging and drug delivery in the brain. The improvement in brain tumor treatment remains dismal despite decades of efforts in drug development and patient care. One of the major obstacles in brain cancer treatment is the poor drug delivery efficiency owing to the unique blood-brain barrier (BBB) in the CNS. Although various anti-cancer agents are available to treat tumors outside of the CNS, the majority fails to cross the BBB. In this regard, nanomedicines have increasingly drawn attention due to their multi-functionality and versatility. Nano drugs can penetrate BBB and other biological barriers, and selectively accumulate in tumor cells, while concurrently decreasing systemic toxicity

Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer

Specific cancer cell targeting is a pre-requisite for efficient drug delivery as well as for high-resolution imaging and still represents a major technical challenge. Tumor-associated enzyme-assisted targeting is a new concept that takes advantage of the presence of a specific activity in the tumor entity. MMP-9 is a protease found to be upregulated in virtually all malignant tumors. Consequently, we hypothesized that its presence can provide a de-shielding activity for targeted delivery of drugs by nanoparticles (NPs) in pancreatic cancer. Here, we describe synthesis and characterization of an optimized MMP-9-cleavable linker mediating specific removal of a PEG shield from a PLGA-b-PEG-based polymeric nanocarrier (Magh@PNPs-PEG-RegaCP-PEG) leading to specific uptake of the smaller PNPs with their cargo into cells. The specific MMP-9-cleavable linker was designed based on the degradation efficiency of peptides derived from the collagen type II sequence. MMP-9-dependent uptake of the Magh@PNPs-PEG-RegaCP-PEG was demonstrated in pancreatic cancer cells in vitro. Accumulation of the Magh@PNPs-PEG-RegaCP-PEG in pancreatic tissues in the clinically relevant KPC mouse model of pancreatic cancer, as a proof-of-concept, was tumor-specific and MMP-9-dependent, indicating that MMP-9 has a strong potential as a specific mediator of PNP de-shielding for tumor-specific uptake. Pre-treatment of mice with Magh@PNPs-PEG-RegaCP-PEG led to reduction of liver metastasis and drastically decreased average colony size. In conclusion, the increased tumor-specific presence and activity of MMP-9 can be exploited to deliver an MMP-9-activatable NP to pancreatic tumors specifically, effectively, and safely.publisher: Elsevier articletitle: Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer journaltitle: Journal of Controlled Release articlelink: http://dx.doi.org/10.1016/j.jconrel.2016.08.016 content_type: article copyright: © 2016 Elsevier B.V. All rights reserved.status: publishe

Matrix metalloproteinase-9 (MMP-9) as an activator of nanosystems for targeted drug delivery in pancreatic cancer (vol 239, pg 39, 2016 )

© 2017 Elsevier B.V. The authors regret that a representative tumor photograph used in Fig. 4B (left) was published in parallel in another study (Grünwald et al., Mol Cancer Res. 2016 Nov; 14(11):1147–1158. doi:10.1158/1541-7786.MCR-16-0180, Epub 2016 Aug 3). The corrected Fig. 4B, containing another representative tumor photograph, appears below. The studies do not contain any overlapping experiments or conclusions. All conclusions drawn in either publication are correct and unaffected by the mistake. The authors apologize for the inconvenience caused.[figure presented] Corrected Fig. 4. Evaluation of MMP-9-dependent uptake of Magh@PNPs-PEG-RegaCP-PEG into pancreatic tumors in vivo. (A) Tumor-specific uptake of Magh@PNPs-PEG-RegaCP-PEG. Prussian Blue staining of PNPs in pancreatic tissue; arrows indicate nanomaterial. Tumor −, Healthy littermates (n = 5); Tumor +, KPC mice (n = 5); Representative images; bars, 100 μm. (B) MMP-9-deficient KPC mice were able to form pancreatic tumors. Left, Representative pancreas whole mount; bar, 1 cm; Right, HE staining of pancreatic sections; representative image; bar, 100 μm. (C) MMP-9- and tumor-dependent uptake of Magh@PNPs-PEG-RegaCP-PEG into pancreatic tissue as determined by Prussian Blue staining-based quantification. Tumor −, Healthy littermates; Tumor +, KPC mice; MMP9 +, wild-type mice; MMP9 −, MMP9 knock-out mice (n = 5 per group). Columns, mean; bars, SEM. One-way ANOVA: n.s., not significant; **p < 0.01; ***p < 0.001.status: publishe