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Polymersomes are an exciting modality for drug delivery due to their structural similarity to biological cells and their ability to encapsulate both hydrophilic and hydrophobic drugs. In this regard, the current work aimed to develop multifunctional polymersomes, integrating dye (with hydrophobic Nile red and hydrophilic sulfo-cyanine5-NHS ester as model drugs) encapsulation, stimulus responsiveness, and surface-ligand modifications. Polymersomes constituting poly(N-2-hydroxypropylmethacrylamide)-b-poly(N-(2-(methylthio)ethyl)acrylamide) (PHPMAm-b-PMTEAM) are prepared by aqueous dispersion RAFT-mediated polymerization-induced self-assembly (PISA). The hydrophilic block lengths have an effect on the obtained morphologies, with short chain P(HPMAm)16 affording spheres and long chain P(HPMAm)43 yielding vesicles. This further induces different responses to H2O2, with spheres fragmenting and vesicles aggregating. Folic acid (FA) is successfully conjugated to the P(HPMAm)43, which self-assembles into FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes. The FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes entrap both hydrophobic Nile red (NR) and hydrophilic Cy5 dye. The NR-loaded FA-linked polymersomes exhibit a controlled release of the encapsulated NR dye when exposed to 10 mM H2O2. All the polymersomes formed are stable in human plasma and well-tolerated in MCF-7 breast cancer cells. These preliminary results demonstrate that, with simple and scalable chemistry, PISA offers access to different shapes and opens up the possibility of the one-pot synthesis of multicompartmental and responsive polymersomes. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most common, malignant and aggressive brain tumour in adults. Despite the use of multimodal treatments, involving surgery, followed by concomitant radiotherapy and chemotherapy, the median survival for patients remains less than 15 months from diagnosis. Low penetration of drugs across the blood-brain barrier (BBB) is a dose-limiting factor for systemic GBM therapies, and as a result, post-surgical intracranial drug delivery strategies are being developed to ensure local delivery of drugs within the brain. Here we describe the effects of PEGylated poly(lactide)-poly(carbonate)-doxorubicin (DOX) nanoparticles (NPs) on the metabolic activity of primary cancer cell lines derived from adult patients following neurosurgical resection, and the commercially available GBM cell line, U87. The results showed that non-drug-loaded NPs were well tolerated at concentrations of up to 100 µg/mL while tumour cell-killing effects were observed for the DOX-NPs at the same concentrations. Further experiments evaluated the release of DOX from polymer-DOX conjugate NPs when incorporated in a thermosensitive in situ gelling poly(DL-lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) matrix paste, in order to simulate the clinical setting of a locally injected formulation for GBM following surgical tumour resection. These assays demonstrated drug release from the polymer pro-drugs, when in PLGA/PEG matrices of two formulations, over clinically relevant time scales. These findings encourage future in vivo assessment of the potential capability of polymer–drug conjugate NPs to penetrate brain parenchyma efficaciously, when released from existing interstitial delivery systems. [ABSTRACT FROM AUTHOR]

Biocompatible and bio-based materials are an appealing resource for the pharmaceutical industry. Poly(glycerol-adipate) (PGA) is a biocompatible and biodegradable polymer that can be used to produce self-assembled nanoparticles (NPs) able to encapsulate active ingredients, with encouraging perspectives for drug delivery purposes. Starch is a versatile, inexpensive, and abundant polysaccharide that can be effectively applied as a bio-scaffold for other molecules in order to enrich it with new appealing properties. In this work, the combination of PGA NPs and starch films proved to be a suitable biopolymeric matrix carrier for the controlled release preparation of hydrophobic drugs. Dynamic Light Scattering (DLS) was used to determine the size of drug-loaded PGA NPs, while the improvement of the apparent drug water solubility was assessed by UV-vis spectroscopy. In vitro biological assays were performed against cancer cell lines and bacteria strains to confirm that drug-loaded PGA NPs maintained the effective activity of the therapeutic agents. Dye-conjugated PGA was then exploited to track the NP release profile during the starch/PGA nanocomposite film digestion, which was assessed using digestion models mimicking physiological conditions. The collected data provide a clear indication of the suitability of our biodegradable carrier system for oral drug delivery. [ABSTRACT FROM AUTHOR]

Starch is one of the most abundant polysaccharides on the earth and it is the most important source of energy intake for humans. Thermoplastic starch (TPS) is also widely used for new bio-based materials. The blending of starch with other molecules may lead to new interesting biodegradable scaffolds to be exploited in food, medical, and pharmaceutical fields. In this work, we used native starch films as biopolymeric matrix carriers of chemo enzymatically-synthesized poly (glycerol-adipate) (PGA) nanoparticles (NPs) to produce a novel and biocompatible material. The prototype films had a crystallinity ranging from 4% to 7%. The intrinsic and thermo-mechanical properties of the composite showed that the incorporation of NPs in the starch films decreases the glass transition temperature. The utilization of these film prototypes as the basis for new biocompatible material showed promise, particularly because they have a very low or even zero cytotoxicity. Coumarin was used to monitor the distribution of the PGA NPs in the films and demonstrated a possible interaction between the two polymers. These novel hybrid nanocomposite films show great promise and could be used in the future as biodegradable and biocompatible platforms for the controlled release of amphiphilic and hydrophobic active ingredients. [ABSTRACT FROM AUTHOR]

Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship between their structure and biological effect. Using tensiometric measurements the critical micelle concentrations (CMCs) of the surfactants were determined and demonstrate that increasing hydrophobic chain length reduces surfactant CMC. In vitro testing on Caco-2 intestinal and Calu-3 airway epithelia revealed that cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, is presented for most of the surfactants at concentrations greater than their CMCs. Further biological study demonstrates that application of cytotoxic concentrations of the surfactants is associated with depolarizing mitochondrial membrane potential, increasing nuclear membrane permeability and activation of effector caspases. It is, therefore, proposed that when applied at cytotoxic levels, the surfactants are inducing apoptosis in both cell lines tested. Importantly, through the culture of epithelial monolayers on Transwell® supports, the surfactants demonstrate the ability to reversibly modulate transepithelial electrical resistance (TEER), and thus open tight junctions, at non-toxic concentrations, emphasizing their potential application as safe permeability enhancers in vivo. [ABSTRACT FROM AUTHOR]

Permeability enhancers are receiving increased attention arising from their ability to increase transepithelial permeability and thus, bioavailability of orally or pulmonary administered biopharmaceutics. Here we present the synthesis and the in vitro assaying of a series of lactose-based non-ionic surfactants, highlighting the relationship between their structure and biological effect. Using tensiometric measurements the critical micelle concentrations (CMCs) of the surfactants were determined and demonstrate that increasing hydrophobic chain length reduces surfactant CMC. In vitro testing on Caco-2 intestinal and Calu-3 airway epithelia revealed that cytotoxicity, assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays, is presented for most of the surfactants at concentrations greater than their CMCs. Further biological study demonstrates that application of cytotoxic concentrations of the surfactants is associated with depolarizing mitochondrial membrane potential, increasing nuclear membrane permeability and activation of effector caspases. It is, therefore, proposed that when applied at cytotoxic levels, the surfactants are inducing apoptosis in both cell lines tested. Importantly, through the culture of epithelial monolayers on Transwell ® supports, the surfactants demonstrate the ability to reversibly modulate transepithelial electrical resistance (TEER), and thus open tight junctions, at non-toxic concentrations, emphasizing their potential application as safe permeability enhancers in vivo.