Polyester nanoparticles delivering chemotherapeutics: Learning from the past and looking to the future to enhance their clinical impact in tumor therapy.

Polymeric nanoparticles (NPs), specifically those comprised of biodegradable and biocompatible polyesters, have been heralded as a game-changing drug delivery platform. In fact, poly(α-hydroxy acids) such as polylactide (PLA), poly(lactide-co-glycolide) (PLGA), and poly(ε-caprolactone) (PCL) have been heavily researched in the past three decades as the material basis of polymeric NPs for drug delivery applications. As materials, these polymers have found success in resorbable sutures, biodegradable implants, and even monolithic, biodegradable platforms for sustained release of therapeutics (e.g., proteins and small molecules) and diagnostics. Few fields have gained more attention in drug delivery through polymeric NPs than cancer therapy. However, the clinical translational of polymeric nanomedicines for treating solid tumors has not been congruent with the fervor or funding in this particular field of research. Here, we attempt to provide a comprehensive snapshot of polyester NPs in the context of chemotherapeutic delivery. This includes a preliminary exploration of the polymeric nanomedicine in the cancer research space. We examine the various processes for producing polyester NPs, including methods for surface-functionalization, and related challenges. After a detailed overview of the multiple factors involved with the delivery of NPs to solid tumors, the crosstalk between particle design and interactions with biological systems is discussed. Finally, we report state-of-the-art approaches toward effective delivery of NPs to tumors, aiming at identifying new research areas and re-evaluating the reasons why some research avenues have underdelivered. We hope our effort will contribute to a better understanding of the gap to fill and delineate the future research work needed to bring polyester-based NPs closer to clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

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. As a monogenetic disorder and lysosomal storage disease affecting the nervous system, the lessons learned from examining nanoparticle delivery to the brain in the context of Krabbe disease can have a broader impact on the treatment of various other neurodevelopmental and neurodegenerative disorders. In this review, we introduce the epidemiology and genetic basis of Krabbe disease, discuss current in vitro and in vivo models of the disease, as well as current therapeutic approaches either approved or at different stage of clinical developments. We then elaborate on challenges in particle delivery to the brain, with a specific emphasis on methods to transport nanomedicines across the blood-brain barrier. We highlight nanoparticles for delivering therapeutics for the treatment of lysosomal storage diseases, classified by the therapeutic payload, including gene therapy, enzyme replacement therapy, and small molecule delivery. Finally, we provide some useful hints on the design of nanomedicines for the treatment of rare neurological disorders.

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. Specifically, potassium hydroxide (KOH) wet etching was used to realize a channel incorporating a series of micropillars (filtering modules) with different geometries and openings, acting as microfilters in the direction of the flow. These filtering modules were designed with progressively decreasing openings, ranging in size from about 5 down to 1 µm. Discoidal polymeric nanoconstructs (DPNs), with a diameter of 5.5 µm and a height of 400 nm, were realized with different poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) ratios (PLGA/PEG), namely, 5:1 and 1:0, resulting in soft and rigid particles, respectively. Given the peculiar geometry of DPNs, the channel height was kept to 5 µm to limit particle tumbling or flipping along the flow. After thorough physicochemical and morphological characterization, DPNs were tested within the microfluidic chip to investigate their behavior under flow. As expected, most rigid DPNs were trapped in the first series of pillars, whereas soft DPNs were observed to cross multiple filtering modules and reach the micropillars with the smallest opening (1 µm). This experimental evidence was also supported by computational tools, where DPNs were modeled as a network of springs and beads immersed in a Newtonian fluid using the smoothed particle hydrodynamics (SPH) method. This preliminary study presents a combined experimental-computational framework to quantify, compare, and analyze the characteristics of particles having complex geometrical and mechanical attributes under flow conditions.

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. In a model of advanced breast cancer lung metastasis, µCGP amplified the colocalization of docetaxel-nanoparticles with pulmonary metastatic foci, prolonged the retention of chemotoxic molecules at the diseased site, suppressed lesion growth, and boosted survival beyond 20 weeks post nodule engraftment. The flexible design and modular architecture of µCGP would allow the efficient deployment of complex combination therapies in other vascular districts too, possibly addressing metastatic diseases of different origins.

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.

Nanoparticle-Cell Interaction: A Cell Mechanics Perspective.

Progress in the field of nanoparticles has enabled the rapid development of multiple products and technologies; however, some nanoparticles can pose both a threat to the environment and human health. To enable their safe implementation, a comprehensive knowledge of nanoparticles and their biological interactions is needed. In vitro and in vivo toxicity tests have been considered the gold standard to evaluate nanoparticle safety, but it is becoming necessary to understand the impact of nanosystems on cell mechanics. Here, the interaction between particles and cells, from the point of view of cell mechanics (i.e., bionanomechanics), is highlighted and put in perspective. Specifically, the ability of intracellular and extracellular nanoparticles to impair cell adhesion, cytoskeletal organization, stiffness, and migration are discussed. Furthermore, the development of cutting-edge, nanotechnology-driven tools based on the use of particles allowing the determination of cell mechanics is emphasized. These include traction force microscopy, colloidal probe atomic force microscopy, optical tweezers, magnetic manipulation, and particle tracking microrheology.