Nanomedicines to treat rare neurological disorders: The case of Krabbe disease.

The brain remains one of the most challenging therapeutic targets due to the low and selective permeability of the blood-brain barrier and complex architecture of the brain tissue. Nanomedicines, despite their relatively large size compared to small molecules and nucleic acids, are being heavily investigated as vehicles to delivery therapeutics into the brain. Here we elaborate on how nanomedicines may be used to treat rare neurodevelopmental disorders, using Krabbe disease (globoid cell leukodystrophy) to frame the discussion.

μMESH-Enabled Sustained Delivery of Molecular and Nanoformulated Drugs for Glioblastoma Treatment.

Modest tissue penetrance, nonuniform distribution, and suboptimal release of drugs limit the potential of intracranial therapies against glioblastoma. Here, a conformable polymeric implant, μMESH, is realized by intercalating a micronetwork of 3 × 5 μm poly(lactic--glycolic acid) (PLGA) edges over arrays of 20 × 20 μm polyvinyl alcohol (PVA) pillars for the sustained delivery of potent chemotherapeutic molecules, docetaxel (DTXL) and paclitaxel (PTXL). Four different μMESH configurations were engineered by encapsulating DTXL or PTXL within the PLGA micronetwork and nanoformulated DTXL (nanoDTXL) or PTXL (nanoPTXL) within the PVA microlayer.

Assessing Differential Particle Deformability under Microfluidic Flow Conditions.

Assessing the mechanical behavior of nano- and micron-scale particles with complex shapes is fundamental in drug delivery. Although different techniques are available to quantify the bulk stiffness in static conditions, there is still uncertainty in assessing particle deformability in dynamic conditions. Here, a microfluidic chip is designed, engineered, and validated as a platform to assess the mechanical behavior of fluid-borne particles.

Boosting the Potential of Chemotherapy in Advanced Breast Cancer Lung Metastasis via Micro-Combinatorial Hydrogel Particles.

Breast cancer cell colonization of the lungs is associated with a dismal prognosis as the distributed nature of the disease and poor permeability of the metastatic foci challenge the therapeutic efficacy of small molecules, antibodies, and nanomedicines. Taking advantage of the unique physiology of the pulmonary circulation, here, micro-combinatorial hydrogel particles (µCGP) are realized via soft lithographic techniques to enhance the specific delivery of a cocktail of cytotoxic nanoparticles to metastatic foci. By cross-linking short poly(ethylene glycol) (PEG) chains with erodible linkers within a shape-defining template, a deformable and biodegradable polymeric skeleton is realized and loaded with a variety of therapeutic and imaging agents, including docetaxel-nanoparticles.

Augmented efficacy of nano-formulated docetaxel plus curcumin in orthotopic models of neuroblastoma.

Neuroblastoma is a biologically heterogeneous extracranial tumor, derived from the sympathetic nervous system, that affects most often the pediatric population. Therapeutic strategies relying on aggressive chemotherapy, surgery, radiotherapy, and immunotherapy have a negative outcome in advanced or recurrent disease. Here, spherical polymeric nanomedicines (SPN) are engineered to co-deliver a potent combination therapy, including the cytotoxic docetaxel (DTXL) and the natural wide-spectrum anti-inflammatory curcumin (CURC).

Boosting the therapeutic efficacy of discoidal nanoconstructs against glioblastoma with rationally designed PEG-Docetaxel conjugates.

Maximizing loading while modulating the release of therapeutic molecules from nanoparticles and implantable drug delivery systems is the key to successfully address deadly diseases like brain cancer. Here, four different conjugates of the potent chemotherapeutic molecule docetaxel (DTXL)were realized to optimize the pharmacological properties of 1,000 × 400 nmDiscoidal PolymericNanoconstructs(DPNs). DTXL was covalently linked to poly-(ethylene) glycol(PEG)chains of different molecular weights, namely 350, 550 and 1,000 Da, and oleic acid (OA).

Shape-specific microfabricated particles for biomedical applications: a review.

The storied history of controlled the release systems has evolved over time; from degradable drug-loaded sutures to monolithic zero-ordered release devices and nano-sized drug delivery formulations. Scientists have tuned the physico-chemical properties of these drug carriers to optimize their performance in biomedical/pharmaceutical applications. In particular, particle drug delivery systems at the micron size regime have been used since the 1980s.

Boosting nanomedicine performance by conditioning macrophages with methyl palmitate nanoparticles.

Surface PEGylation, biological camouflage, shape and stiffness modulation of nanoparticles as well as liver blockade and macrophage depletion have all improved the blood longevity of nanomedicines. Yet, the mononuclear phagocytic system still recognizes, sequesters, and processes the majority of blood borne particles. Here, the natural fatty acid methyl palmitate is combined with endogenous blood components - albumin - realizing ∼200 nm stable, spherical nanoparticles (MPN) capable of inducing a transient and reversible state of dormancy into macrophages.

Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours.

The poor transport of molecular and nanoscale agents through the blood-brain barrier together with tumour heterogeneity contribute to the dismal prognosis in patients with glioblastoma multiforme. Here, a biodegradable implant (μMESH) is engineered in the form of a micrometre-sized poly(lactic-co-glycolic acid) mesh laid over a water-soluble poly(vinyl alcohol) layer. Upon poly(vinyl alcohol) dissolution, the flexible poly(lactic-co-glycolic acid) mesh conforms to the resected tumour cavity as docetaxel-loaded nanomedicines and diclofenac molecules are continuously and directly released into the adjacent tumour bed.

A permeable on-chip microvasculature for assessing the transport of macromolecules and polymeric nanoconstructs.

Hypothesis: The selective permeation of molecules and nanomedicines across the diseased vasculature dictates the success of a therapeutic intervention. Yet, in vitro assays cannot recapitulate relevant differences between the physiological and pathological microvasculature. Here, a double-channel microfluidic device was engineered to comprise vascular and extravascular compartments connected through a micropillar membrane with tunable permeability.

Roadmap on nanomedicine.

Since the launch of the Alliance for Nanotechnology in Cancer by the National Cancer Institute in late 2004, several similar initiatives have been promoted all over the globe with the intention of advancing the diagnosis, treatment and prevention of cancer in the wake of nanoscience and nanotechnology. All this has encouraged scientists with diverse backgrounds to team up with one another, learn from each other, and generate new knowledge at the interface between engineering, physics, chemistry and biomedical sciences. Importantly, this new knowledge has been wisely channeled towards the development of novel diagnostic, imaging and therapeutic nanosystems, many of which are currently at different stages of clinical development.

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells.

Fine-tuning loading and release of therapeutic and imaging agents associated with polymeric matrices is a fundamental step in the preclinical development of novel nanomedicines. Here, 1,000 × 400 nm Discoidal Polymeric Nanoconstructs (DPNs) were realized via a top-down, template-based fabrication approach, mixing together poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-diacrylate (PEG-DA) chains in a single polymer paste. Two different loading strategies were tested, namely the "direct loading" and the "absorption loading.

Erythrocyte-Inspired Discoidal Polymeric Nanoconstructs Carrying Tissue Plasminogen Activator for the Enhanced Lysis of Blood Clots.

Tissue plasminogen activator (tPA) is the sole approved therapeutic molecule for the treatment of acute ischemic stroke. Yet, only a small percentage of patients could benefit from this life-saving treatment because of medical contraindications and severe side effects, including brain hemorrhage, associated with delayed administration. Here, a nano therapeutic agent is realized by directly associating the clinical formulation of tPA to the porous structure of soft discoidal polymeric nanoconstructs (tPA-DPNs).

Modulating Phagocytic Cell Sequestration by Tailoring Nanoconstruct Softness.

The effect of nanoparticle size, shape, and surface properties on cellular uptake has been extensively investigated for its basic science and translational implications. Recently, softness is emerging as a design parameter for modulating the interaction of nanoparticles with cells and the biological microenvironment. Here, circular, quadrangular, and elliptical polymeric nanoconstructs of different sizes are realized with a Young's modulus ranging from ∼100 kPa (soft) to 10 MPa (rigid).

Ameliorating Amyloid-β Fibrils Triggered Inflammation Curcumin-Loaded Polymeric Nanoconstructs.

Inflammation is a common hallmark in several diseases, including atherosclerosis, cancer, obesity, and neurodegeneration. In Alzheimer's disease (AD), growing evidence directly correlates neuronal damage with inflammation of myeloid brain cells, such as microglia. Here, polymeric nanoparticles were engineered and characterized for the delivery of anti-inflammatory molecules to macrophages stimulated via direct incubation with amyloid-β fibers.

Deformable Discoidal Polymeric Nanoconstructs for the Precise Delivery of Therapeutic and Imaging Agents.

Over the last 15 years, a plethora of materials and different formulations have been proposed for the realization of nanomedicines. Yet drug-loading efficiency, sequestration by phagocytic cells, and tumor accumulation are sub-optimal. This would imply that radically new design approaches are needed to propel the clinical integration of nanomedicines, overcoming well-accepted clichés.

Soft Discoidal Polymeric Nanoconstructs Resist Macrophage Uptake and Enhance Vascular Targeting in Tumors.

Most nanoparticles for biomedical applications originate from the self-assembling of individual constituents through molecular interactions and possess limited geometry control and stability. Here, 1000 × 400 nm discoidal polymeric nanoconstructs (DPNs) are demonstrated by mixing hydrophobic and hydrophilic polymers with lipid chains and curing the resulting paste directly within silicon templates. By changing the paste composition, soft- and rigid-DPNs (s- and r-DPNs) are synthesized exhibiting the same geometry, a moderately negative surface electrostatic charge (-14 mV), and different mechanical stiffness (∼1.

Hierarchically-Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation.

Iron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging; guidance under remote fields; heat generation; and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers.

Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors.

Background: Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport.