Templated Reactive Crystallization of Active Pharmaceutical Ingredient in Hydrogel Microparticles Enabling Robust Drug Product Processing.

Commercialization of most promising active pharmaceutical ingredients (APIs) is impeded either by poor bioavailability or challenging physical properties leading to costly manufacture. Bioavailability of ionizable hydrophobic APIs can be enhanced by its conversion to salt form. While salt form of the API presents higher solution concentration than the non-ionized form, poor physical properties resulting from particle anisotropy or non-ideal morphology (needles) and particle size distribution not meeting dissolution rate targets can still inhibit its commercial translation. In this regard, API physical properties can be improved through addition of non-active components (excipients or carriers) during API manufacture. In this work, a facile method to perform reactive crystallization of an API salt in presence of the microporous environment of a hydrogel microparticle is presented. Specifically, the reaction between acidic antiretroviral API, raltegravir and base potassium hydroxide is performed in the presence of polyethylene glycol diacrylamide hydrogel microparticles. In this bottom-up approach, the spherical template hydrogel microparticles for the reaction lead to monodisperse composites loaded with inherently micronized raltegravir-potassium crystals, thus improving API physical properties without hampering bioavailability. Overall, this technique provides a novel approach to reactive crystallization while maintaining the API polymorph and crystallinity.

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. Recent advances in micro and nanofabrication techniques have enabled precise control of particle size and geometry-here we review the utility of microplates and discoidal polymeric particles for a range of pharmaceutical applications. Microplates are defined as micrometer scale polymeric local depot devices in cuboid form, while discoidal polymeric nanoconstructs are disk-shaped polymeric particles having a cross-sectional diameter in the micrometer range and a thickness in the hundreds of nanometer range. These versatile particles can be used to treat several pathologies such as cancer, inflammatory diseases and vascular diseases, by leveraging their size, shape, physical properties (e.g., stiffness), and component materials, to tune their functionality. This review highlights design and fabrication strategies for these particles, discusses their applications, and elaborates on emerging trends for their use in formulations.

Synthesis of Uniform Polymer Encapsulated Organic Nanocrystals through Ouzo Nanocrystallization.

Nanocrystals (NCs) are widely used in optoelectronics, photocatalysis, and bioimaging. As the surface area to volume ratio increases with a decrease in the size of NCs, strategies to control the size of NCs are highly valuable for many applications. Given the importance of photoluminescent dyes, especially those with aggregation-induced emission, the transformation from an amorphous to a crystalline state can yield a drastic enhancement in their optical properties, which is of significance for biomedical applications. Till now, there is no general method available for the synthesis of small NCs with accurate control over the size and uniformity. Herein, a simple and general approach of ouzo nanocrystallization is presented for the synthesis of small (<100 nm) and highly uniform (polydispersity index~0.1) NCs with good control over the size. The process of nanoprecipitation is used to synthesize uniform nanoparticles (NPs) with different size, which is followed by solvent addition to form swollen NPs. Further, the amorphous core of swollen NPs is converted into NCs within polymer shell under Ouzo zone, which restricts NCs to grow above certain size. To demonstrate the general applicability of ouzo nanocrystallization, two different classes of luminescent materials are used as examples to fabricate small and highly uniform NCs.

Preparation of anisotropic multiscale micro-hydrogels via two-photon continuous flow lithography.

HYPOTHESIS: Polymeric anisotropic soft microparticles show interesting behavior in biological environments and hold promise for drug delivery and biomedical applications. However, self-assembly and substrate-based lithographic techniques are limited by low resolution, batch operation or specific particle geometry and deformability. Two-photon polymerization in microfluidic channels may offer the required resolution to continuously fabricate anisotropic micro-hydrogels in sub-10 µm size-range. EXPERIMENTS: Here, a pulsed laser source is used to perform two-photon polymerization under microfluidic flow of a poly(ethylene glycol) diacrylate (PEGDA) solution with the objective of realizing anisotropic micro-hydrogels carrying payloads of various nature, including small molecules and nanoparticles. The fabrication process is described via a reactive-convective-diffusion system of equations, whose solution under proper auxiliary conditions is used to corroborate the experimental observations and sample the configuration space. FINDINGS: By tuning the flow velocity, exposure time and pre-polymer composition, anisotropic PEGDA micro-hydrogels are obtained in the 1-10 µm size-range and exhibit an aspect ratio varying from 1 to 5. Furthermore, 200 nm curcumin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and 100 nm ssRNA-encapsulating lipid nanoparticles were entrapped within square PEGDA micro-hydrogels. The proposed approach could support the fabrication of micro-hydrogels of well-defined morphology, stiffness, and surface properties for the sustained release of therapeutic agents.

Stereoisomerization during Molecular Packing.

Isomerization is an essential chemical process that often evokes dramatic change of chemical, physical, or biological properties. For a long time, isomerization has been known as a transformation that is induced by certain external energy such as light, heat, or mechanical force. Herein, a new isomerization phenomenon is described, which does not require external energy but simply occurs during molecular packing. The proposed isomerization is demonstrated by a series of symmetric donor-acceptor-donor (D-A-D) molecules, the donor of which may adopt two different stereoisomeric forms. Based on the evidence of the asymmetric isomers in crystals, the occurrence of isomerization during molecular packing is proved. Moreover, the unique asymmetric geometry in the solid state favors the restriction of intramolecular motion, resulting in highly efficient organic solids with quantum yields approaching unity.

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. This roadmap collects eight brief articles elaborating on the interaction of nanomedicines with human biology; the biomedical and clinical applications of nanomedicines; and the importance of patient stratification in the development of future nanomedicines. The first article reports on the role of geometry and mechanical properties in nanomedicine rational design; the second articulates on the interaction of nanomedicines with cells of the immune system; and the third deals with exploiting endogenous molecules, such as albumin, to carry therapeutic agents. The second group of articles highlights the successful application of nanomedicines in the treatment of cancer with the optimal delivery of nucleic acids, diabetes with the sustained and controlled release of insulin, stroke by using thrombolytic particles, and atherosclerosis with the development of targeted nanoparticles. Finally, the last contribution comments on how nanomedicine and theranostics could play a pivotal role in the development of personalized medicines. As this roadmap cannot cover the massive extent of development of nanomedicine over the past 15 years, only a few major achievements are highlighted as the field progressively matures from the initial hype to the consolidation phase.

Mechanistic Understanding of the Biological Responses to Polymeric Nanoparticles.

Polymeric nanoparticles play important roles in the delivery of a multitude of therapeutic and imaging contrast agents. Although these nanomaterials have shown tremendous potential in disease diagnosis and therapy, there have been many reports on the failure of these nanoparticles in realizing their intended objectives due to an individual or a combination of factors, which have collectively challenged the merit of nanomedicine for disease theranostics. Herein, we investigate the interactions of polymeric nanoparticles with biological entities from molecular to organism levels. Specifically, the protein corona formation, in vitro endothelial uptake, and in vivo circulation time of these nanoparticles are systematically probed. We identify the crucial role of nanocarrier lipophilicity, zeta-potential, and size in controlling the interactions between nanoparticles and biological systems and propose a two-step framework in formulating a single nanoparticle system to regulate multiple biological effects. This study provides insight into the rational design and optimization of the performance of polymeric nanoparticles to advance their theranostic and nanomedicine applications.

Cancer-Cell-Activated Photodynamic Therapy Assisted by Cu(II)-Based Metal-Organic Framework.

Activation of photosensitizers (PSs) in targeted lesion and minimization of reactive oxygen species (ROS) depletion by endogenous antioxidants constitute promising approaches to perform highly effective image-guided photodynamic therapy (PDT) with minimal non-specific phototoxicity. Traditional strategies to fabricate controllable PS platforms rely on molecular design, which requires specific modification of each PS before PDT. Therefore, construction of a general tumor-responsive PDT platform with minimum ROS loss from endogenous antioxidant, typically glutathione (GSH), is highly desirable. Herein, MOF-199, a Cu(II) carboxylate-based metal-organic framework (MOF), is selected to serve as an inert carrier to load PSs with prohibited photosensitization during delivery. After cellular uptake, Cu (II) in the MOFs effectively scavenges endogenous GSH, concomitantly induces decomposition of MOF-199 to release the encapsulated PSs, and recovers their ROS generation. In vitro and in vivo experiments demonstrate highly effective cancer cell ablation and anticancer PDT with diminished normal cell phototoxicity. This strategy is generally applicable to PSs with both aggregation-induced emission and aggregation-caused quenching to implement activatable and enhanced image-guided PDT.

Polymerization-Enhanced Two-Photon Photosensitization for Precise Photodynamic Therapy.

Two-photon excited photodynamic therapy (2PE-PDT) has attracted great attention in recent years due to its great potential for deep-tissue and highly spatiotemporally precise cancer therapy. Photosensitizers (PSs) with high singlet oxygen (1O2) generation efficiency and large two-photon absorption (2PA) cross-sections are highly desirable, but the availability of such PSs is limited by challenges in molecular design. In this work, we report that the polymerization of small-molecule PSs with aggregation-induced emission (AIE) could yield conjugated polymer PSs with good brightness, high 1O2 generation efficiency, and large 2PA cross-sections. A pair of conjugated polymer PSs were designed and synthesized, and the corresponding AIE PS dots were prepared by nanoprecipitation, which exhibited outstanding 2PE-PDT performance in in vitro cancer cell ablation and in vivo zebrafish liver tumor treatment. Our work highlights a strategy to design highly efficient PSs for 2PE-PDT.