Denis Cecchin

Polymersome-Mediated Delivery of Combination Anticancer Therapy to Head and Neck Cancer Cells: 2D and 3D in Vitro Evaluation

Polymersomes have the potential to encapsulate and deliver chemotherapeutic drugs into tumor cells, reducing off-target toxicity that often compromises anticancer treatment. Here, we assess the ability of the pH-sensitive poly 2-(methacryloyloxy)ethyl phosphorylcholine (PMPC)- poly 2-(diisopropylamino)ethyl methacrylate (PDPA) polymersomes to encapsulate chemotherapeutic agents for effective combinational anticancer therapy. Polymersome uptake and ability to deliver encapsulated drugs into healthy normal oral cells and oral head and neck squamous cell carcinoma (HNSCC) cells was measured in two and three-dimensional culture systems. PMPC-PDPA polymersomes were more rapidly internalized by HNSCC cells compared to normal oral cells. Polymersome cellular uptake was found to be mediated by class B scavenger receptors. We also observed that these receptors are more highly expressed by cancer cells compared to normal oral cells, enabling polymersome-mediated targeting. Doxorubicin and paclitaxel were encapsulated into pH-sensitive PMPC-PDPA polymersomes with high efficiencies either in isolation or as a dual-load for both singular and combinational delivery. In monolayer culture, only a short exposure to drug-loaded polymersomes was required to elicit a strong cytotoxic effect. When delivered to three-dimensional tumor models, PMPC-PDPA polymersomes were able to penetrate deep into the center of the spheroid resulting in extensive cell damage when loaded with both singular and dual-loaded chemotherapeutics. PMPC-PDPA polymersomes offer a novel system for the effective delivery of chemotherapeutics for the treatment of HNSCC. Moreover, the preferential internalization of PMPC polymersomes by exploiting elevated scavenger receptor expression on cancer cells opens up the opportunity to target polymersomes to tumors.

Enhanced drug delivery to melanoma cells using PMPC-PDPA polymersomes

We present the efficient and stable encapsulation of doxorubicin within pH sensitive polymeric vesicles (polymersomes) for intracellular and nuclear delivery to melanoma cells. We demonstrate that PMPC25-PDPA70 polymersomes can encapsulate doxorubicin for long periods of time without significant drug release. We demonstrate that empty polymersomes are non-toxic and that they are quickly and more efficiently internalised by melanoma cells compared to healthy cells. Encapsulated doxorubicin has a strong cytotoxic effect on both healthy and cancerous cells, but when encapsulated it had a preferential effect on melanoma cells indicating that this formulation can be used to achieve an enhanced drug delivery to cancerous cells rather than to the healthy surrounding cells.

Chemotactic synthetic vesicles: Design and applications in blood-brain barrier crossing

Brain homing nanoswimmers: Glucose-fueled propulsion combined with blood-brain barrier crossing enhances brain delivery. In recent years, scientists have created artificial microscopic and nanoscopic self-propelling particles, often referred to as nano- or microswimmers, capable of mimicking biological locomotion and taxis. This active diffusion enables the engineering of complex operations that so far have not been possible at the micro- and nanoscale. One of the most promising tasks is the ability to engineer nanocarriers that can autonomously navigate within tissues and organs, accessing nearly every site of the human body guided by endogenous chemical gradients. We report a fully synthetic, organic, nanoscopic system that exhibits attractive chemotaxis driven by enzymatic conversion of glucose. We achieve this by encapsulating glucose oxidase alone or in combination with catalase into nanoscopic and biocompatible asymmetric polymer vesicles (known as polymersomes). We show that these vesicles self-propel in response to an external gradient of glucose by inducing a slip velocity on their surface, which makes them move in an extremely sensitive way toward higher-concentration regions. We finally demonstrate that the chemotactic behavior of these nanoswimmers, in combination with LRP-1 (low-density lipoprotein receptor–related protein 1) targeting, enables a fourfold increase in penetration to the brain compared to nonchemotactic systems.

Biomimetic Hybrid Nanocontainers with Selective Permeability

Abstract Chemistry plays a crucial role in creating synthetic analogues of biomacromolecular structures. Of particular scientific and technological interest are biomimetic vesicles that are inspired by natural membrane compartments and organelles but avoid their drawbacks, such as membrane instability and limited control over cargo transport across the boundaries. In this study, completely synthetic vesicles were developed from stable polymeric walls and easy‐to‐engineer membrane DNA nanopores. The hybrid nanocontainers feature selective permeability and permit the transport of organic molecules of 1.5 nm size. Larger enzymes (ca. 5 nm) can be encapsulated and retained within the vesicles yet remain catalytically active. The hybrid structures constitute a new type of enzymatic nanoreactor. The high tunability of the polymeric vesicles and DNA pores will be key in tailoring the nanocontainers for applications in drug delivery, bioimaging, biocatalysis, and cell mimicry.

Translocation of flexible polymersomes across pores at the nanoscale

Hierarchical biological systems such as tissues and organs are often characterised by highly crowded and packed environments with nanoscopic interconnections between them. Engineering nanovectors that can penetrate and diffuse across these is critical to ensure enhanced delivery and targeting. Here we demonstrate that flexible polymeric vesicles, known as polymersomes, enable the translocation of large macromolecules across both synthetic and biological porous systems. We compare the translocation across narrow pores of different polymersome formulations. We demonstrate that effective translocation depends on the right combination of mechanical properties and surface lubrication. We prove that with the effect of external gradients (e.g. osmotic pressure, capillarity, hydration, etc.) polymersomes can translocate across pores with diameters one order of magnitude smaller without breaking. We demonstrate that these properties are essential to develop effective tissue penetration and show polymersome mediated transdermal delivery of large macromolecules such as dextran and antibodies using human ex vivo skin.

Active delivery to the brain by chemotaxis

One of the most promising tasks is the ability to engineer nanocarriers that can autonomously navigate within tissues and organs, accessing nearly every site of the human body guided by endogenous chemical gradients. Here we report a fully synthetic, organic, nanoscopic system that exhibits attractive chemotaxis driven by enzymatic conversion of glucose. We achieve this by encapsulating glucose oxidase, alone or in combination with catalase, into nanoscopic and biocompatible asymmetric polymer vesicles (known as polymersomes). We show that these vesicles self-propel in response to an external gradient of glucose by inducing a slip velocity on their surface, which makes them move in an extremely sensitive way towards higher concentration regions. We finally demonstrate that the chemotactic behaviour of these nanoswimmers enables a four-fold increase in penetration to the brain compared to non-chemotactic systems.In recent years, scientists have created artificial microscopic and nanoscopic self-propelling particles, often referred to as nano- or micro-swimmers, capable of mimicking biological locomotion and taxis. This active diffusion enables the engineering of complex operations that so far have not been possible at the micro- and nanoscale. One of the most promising task is the ability to engineer nanocarriers that can autonomously navigate within tissues and organs, accessing nearly every site of the human body guided by endogenous chemical gradients. Here we report a fully synthetic, organic, nanoscopic system that exhibits attractive chemotaxis driven by enzymatic conversion of glucose. We achieve this by encapsulating glucose oxidase — alone or in combination with catalase — into nanoscopic and biocompatible asymmetric polymer vesicles (known as polymersomes). We show that these vesicles self-propel in response to an external gradient of glucose by inducing a slip velocity on their surface, which makes them move in an extremely sensitive way towards higher concentration regions. We finally demonstrate that the chemotactic behaviour of these nanoswimmers enables a four-fold increase in penetration to the brain compared to non-chemotactic systems.