Brain cancer, especially the most common type of glioblastoma, is highly invasive and known as one of the most devastating and deadly neoplasms. Despite surgical and medical advances, the prognosis for most brain cancer patients remains dismal and the median survival rarely exceeds 16 months. Drug delivery to the brain is significantly hindered by the existence of the blood–brain barrier (BBB), which serves as a protective semi-permeable membrane for the central nervous system. Recent breakthroughs in nanotechnology have yielded multifunctional theranostic nanoplatforms with the ability to cross or bypass the BBB, enabling accurate diagnosis and effective treatment of brain tumours. Herein, we make our efforts to present a comprehensive review on the latest remarkable advances in BBB-crossing nanotechnology, with an emphasis on the judicious design of multifunctional nanoplatforms for effective BBB penetration, efficient tumour accumulation, precise tumour imaging, and significant tumour inhibition of brain cancer. The detailed elucidation of BBB-crossing nanotechnology in this review is anticipated to attract broad interest from researchers in diverse fields to participate in the establishment of powerful BBB-crossing nanoplatforms for highly efficient brain cancer theranostics.

Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics

We report on the solution-state assembly of all-conjugated polythiophene diblock copolymers containing nonpolar (hexyl) and polar (triethylene glycol) side chains. The polar substituents provide a large contrast in solubility, enabling formation of stably suspended crystalline fibrils even under very poor solvent conditions for the poly(3-hexylthiophene) block. For appropriate block ratios, complexation of the triethylene glycol side chains with added potassium ions drives the formation of helical nanowires that further bundle into superhelical structures.

http://absimage.aps.org/image/MAR11/MWS_MAR11-2010-005155.pdf

Hierarchical Helical-Assembly of Conjugated Poly(3-hexylthiophene)- b-poly(3-triethylene glycol-thiophene) Diblock Copolymers

A major obstacle facing brain diseases such as Alzheimer's disease, multiple sclerosis, brain tumors, and strokes is the blood-brain barrier (BBB). The BBB prevents the passage of certain molecules and pathogens from the circulatory system into the brain. Therefore, it is nearly impossible for therapeutic drugs to target the diseased cells without the assistance of carriers. Nanotechnology is an area of growing public interest; nanocarriers, such as polymer-based, lipid-based, and inorganic-based nanoparticles can be engineered in different sizes, shapes, and surface charges, and they can be modified with functional groups to enhance their penetration and targeting capabilities. Hence, understanding the interaction between nanomaterials and the BBB is crucial. In this Review, the components and properties of the BBB are revisited and the types of nanocarriers that are most commonly used for brain drug delivery are discussed. The properties of the nanocarriers and the factors that affect drug delivery across the BBB are elaborated upon in this review. Additionally, the most recent developments of nanoformulations and nonconventional drug delivery strategies are highlighted. Finally, challenges and considerations for the development of brain targeting nanomedicines are discussed. The overall objective is to broaden the understanding of the design and to develop nanomedicines for the treatment of brain diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/smll.201801588

Drug Delivery to the Brain across the Blood–Brain Barrier Using Nanomaterials

Interest in increasing drug delivery efficiency has risen over the past decade both as a means to improve efficacy of already clinically available drugs and due to the increased difficulties of approving new drugs. As a functional group for targeted drug delivery, boronic acids (BAs) have been incorporated in polymeric particles both as a stimuli-responsive functional group and as a targeting ligand. Here, BA chemistry presents a wealth of opportunities for biological applications. It not only reacts with several chemical markers of disease such as reactive oxygen species (ROS), adenosine triphosphate (ATP), glucose, and reduced pH, but it also acts as ligands for diols such as sialic acid. These stimuli-responsive drug delivery systems optimize delivery of therapeutics based on rational design and precise molecular engineering. When designing materials containing BA, the unique chemical properties are important to take into consideration such as its vacant p-orbital, its molecular geometry, and the designed acid's pKa. Instead of behaving as most carboxylic acids that donate protons, BAs instead primarily act as Lewis acids that accept electrons. In aqueous solution, most polymers containing BA exist in an equilibrium between their triangular hydrophobic form and a tetrahedral hydrophilic form. The most common pKa's are in the nonphysiological range of 8-10, and much ongoing research focuses on modifying BAs into materials sensitive to a more physiologically relevant pH range. So far, BA moieties have been incorporated into a stunning array of materials, ranging from small molecules that can self-assemble into higher order structures such as micelles and polymeric micelles, via larger polymeric assemblies, to large scale hydrogels. With the abundance of biological molecules containing diols and polyhydroxy motifs, BA-containing materials have proven valuable in several biomedical applications such as treatment of cancer, diabetes, obesity, and bacterial infections. Both materials functionalized with BA and boronic esters display good safety profiles in vitro and in vivo; thus, BA-containing materials represent promising carriers for responsive delivery systems with great potential for clinical translation. The intention of this Account is to showcase the versatility of BA for biomedical applications. We first discuss the chemistry of BA and what to consider when designing BA-containing materials. Further, we review how its chemistry recently has been applied to nanomaterials for enhanced delivery efficiency, both as a stimuli-responsive group and as a targeting ligand. Lastly, we discuss the current limitations and further perspectives of BA in biomaterials, based on the great benefits that can come from utilizing the unique BA chemistry to enhance drug delivery efficiency.

The Chemistry of Boronic Acids in Nanomaterials for Drug Delivery.

Recent studies have revealed the effects of shape on in vivo nanoparticle circulation, distribution, extravasation, and cellular uptake. Morphology is therefore becoming a key factor to be considered in the rational design of nanoparticulate systems for specific biomedical applications such as targeted drug delivery. Technologies for reliable and scalable fabrication of shape-specific micro- and nanoparticles are emerging, which will allow further investigations into this crucial parameter that is poised to substantially impact nanomedicine.

Non-spherical micro- and nanoparticles in nanomedicine

Conjugated polymer nanoparticles in aqueous media have received much attention because of their specific electronic, optical and medicinal properties. However, flexible hydrophilic chains such as oligo(ethylene oxide) groups on the outer surface of the nanoparticles may induce increases in the particle size resulting from the aggregation of nanoparticles in water. We designed a bolaamphiphilic monomer to produce polythiophene nanoparticles. The resulting nanoparticles exhibit multichromic responses to solvent, temperature and acid/base that can be detected by the naked eye. The nanoparticles, with an average diameter of 170 nm and a large zeta potential of −66.6 mV, remain stable in tetrahydrofuran/water mixtures even after 8 months. As the concentration of water increases, the nanoparticles turn from yellow to violet because the molecular conformation of the thiophene units changes. The nanoparticles dispersed in water display a reversible thermochromic response between 20 and 90 °C, which originates from their different morphologies of an amorphous solid below and an isotropic liquid above their melting point of 60 °C. Adding hydrobromic acid yields an almost colorless dispersion because of the formation of polarons (p-doping), and the nanoparticles revert to their initial violet dispersion upon bubbling with ammonia gas owing to the dedoping of the polythiophene nanoparticles.

Polythiophene nanoparticles that display reversible multichromism in aqueous media

One-pot heterocyclic ring closure of 1,1′-bi-2-naphthol to 7H-dibenzo[c,g]carbazole

A new type of turn-on electrochemical protein detection is developed using an electropolymerizable molecular probe. To detect trypsin, a benzamidine ligand is conjugated with a thiophene moiety. Encapsulation of the probe in the trypsin pocket prevents electropolymerization, leading to efficient electron transfer from the electrolyte to the electrode. In contrast, unbound probes can become electropolymerized, yielding a polythiophene layer on the electrode. The polythiophene formed this way suppressed electron transfer. The detection limit of trypsin using this electrochemical strategy is 50 nM. The method is shown to be useful for nonenzymatic turn-on electrochemical detection.

Thiophene-Conjugated Ligand Probe for Nonenzymatic Turn-On Electrochemical Protein Detection

Toward renewable energy for global leveling, compounds that can store ammonia (NH3), a carbon-free energy carrier of hydrogen, will be of great value. Here, we report an organic-inorganic halide perovskite compound that can chemically store NH3 through dynamic structural transformation. Upon NH3 uptake, a chemical structure change occurs from a one-dimensional columnar structure to a two-dimensional layered structure by addition reaction. NH3 uptake is estimated to be 10.2 mmol g-1 at 1 bar and 25 °C. In addition, NH3 extraction can be performed by a condensation reaction at 50 °C under vacuum. X-ray diffraction analysis reveals that reversible NH3 uptake/extraction originates from a cation/anion exchange reaction. This structural transformation shows the potential to integrate efficient uptake and extraction in a hybrid perovskite compound through chemical reaction. These findings will pave the way for further exploration of dynamic, reversible, and functionally useful compounds for chemical storage of NH3.

Krishnachary Salikolimi

Papers

Polythiophene nanoparticles that display reversible multichromism in aqueous media

One-pot heterocyclic ring closure of 1,1′-bi-2-naphthol to 7H-dibenzo[c,g]carbazole

Thiophene-Conjugated Ligand Probe for Nonenzymatic Turn-On Electrochemical Protein Detection

Chemical Storage of Ammonia through Dynamic Structural Transformation of a Hybrid Perovskite Compound.