Animal models are effective for assessing tumor localization of nanosystems but difficult to use for studying penetration beyond the vasculature. Here, we have used well-characterized HCT116 ...colorectal cancer spheroids to study the effect of nanoparticle (NP) physicochemical properties on penetration and uptake. Incubation of spheroids with Hoechst 33342 resulted in a dye gradient, which facilitated discrimination between the populations of cells in the core and at the periphery of spheroids by flow cytometry. This approach was used to compare doxorubicin and liposomal doxorubicin (Caelyx) and a range of model poly(styrene) nanoparticles of different sizes (30 nm, 50 nm, 100 nm) and with different surface chemistries (50 nm uniform plain, carboxylated, aminated and a range of NPs and polyethylene glycol modified NPs prepared from a promising new functionalized biodegradable polymer (poly(glycerol-adipate), PGA). Unmodified poly(styrene) nanoparticles (30 nm/50 nm) were able to penetrate to the core of HCT116 spheroids more efficiently than larger poly(styrene) nanoparticles (100 nm). Surprisingly, penetration of 30 and 50 nm particles was as good as clinically relevant doxorubicin concentrations. However, penetration was reduced with higher surface charge. PGA NPs of 100 nm showed similar penetration into spheroids as 50 nm poly(styrene) nanoparticles, which may be related to polymer flexibility. PEG surface modification of polymeric particles significantly improved penetration into the spheroid core. The new model combining the use of spheroids Hoechst staining and flow cytometry was a useful model for assessing NP penetration and gives useful insights into the effects of NPs’ physical properties when designing nanomedicines.
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IJS, KILJ, NUK, PNG, UL, UM
Nanoparticle (NP) drug delivery systems are known to potentially enhance the efficacy of therapeutic agents. As for antimicrobial drugs, therapeutic solutions against drug-resistant microbes are ...urgently needed due to the worldwide antimicrobial resistance issue. Usnic acid is a widely investigated antimicrobial agent suffering from poor water solubility. In this study, polymer nanoparticles based on polyglycerol adipate (PGA) grafted with polycaprolactone (PCL) were developed as carriers for usnic acid. We demonstrated the potential of the developed systems in ensuring prolonged bactericidal activity against a model bacterial species,
. The macromolecular architecture changes produced by PCL grafted from PGA significantly influenced the drug release profile and mechanism. Specifically, by varying the length of PCL arms linked to the PGA backbone, it was possible to tune the drug release from a burst anomalous drug release (high PCL chain length) to a slow diffusion-controlled release (low PCL chain length). The developed nanosystems showed a prolonged antimicrobial activity (up to at least 7 days) which could be used in preventing/treating infections occurring at different body sites, including medical device-related infection and mucosal/skin surface, where Gram-positive bacteria are commonly involved.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Polymer–drug conjugates have received considerable attention over the last decades due to their potential for improving the clinical outcomes for a range of diseases. It is of importance to develop ...methods for their preparation that have simple synthesis and purification requirements but maintain high therapeutic efficacy and utilize macromolecules that can be cleared via natural excretory pathways upon breakdown. Herein, the combination of ring‐opening polymerization (ROP) and reversible addition−fragmentation chain‐transfer (RAFT) polymerization is described for the straightforward synthesis of amphiphilic, stimuli‐responsive, biodegradable, and highly functionalizable hyperbranched polymers. These unimolecular nanoparticles demonstrate a versatile platform for the synthesis of polymer–drug conjugates owing to the inclusion of a Boc‐protected polycarbonate moiety in either a block or random copolymer formation. A proof‐of‐concept study on the complexation of the poorly water‐soluble antimicrobial drug usnic acid results in polymer‐drug complexes with powerful antimicrobial properties against gram‐positive bacteria. Therefore, this work highlights the potential of amphiphilic and biodegradable hyperbranched polymers for antimicrobial applications.
This work describes the combination of ring‐opening and reversible addition−fragmentation chain‐transfer polymerizations for the straightforward synthesis of amphiphilic, biodegradable, and highly functionalizable hyperbranched polymers. These unimolecular nanoparticles could complex the poorly water‐soluble antimicrobial drug usnic acid, resulting in polymer–drug complexes with powerful antimicrobial properties against gram‐positive bacteria, highlighting the potential of amphiphilic and biodegradable hyperbranched polymers for antimicrobial applications
.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Segmented polyurethane ionomers find prominent applications in the biomedical field since they can combine the good mechanical and biostability properties of polyurethanes (PUs) with the strong ...hydrophilicity features of ionomers. In this work, PU ionomers were prepared from a carboxylated diol, poly(tetrahydrofuran) (soft phase) and a small library of diisocyanates (hard phase), either aliphatic or aromatic. The synthesized PUs were characterized to investigate the effect of ionic groups and the nature of diisocyanate upon the structure–property relationship. Results showed how the polymer hard/soft phase segregation was affected by both the concentration of ionic groups and the type of diisocyanate. Specifically, PUs obtained with aliphatic diisocyanates possessed a hard/soft phase segregation stronger than PUs with aromatic diisocyanates, as well as greater bulk and surface hydrophilicity. In contrast, a higher content of ionic groups per polymer repeat unit promoted phase mixing. The neutralization of polymer ionic groups with silver or zinc further increased the hard/soft phase segregation and provided polymers with antimicrobial properties. In particular, the Zinc/PU hybrid systems possessed activity only against the Gram-positive Staphylococcus epidermidis while Silver/PU systems were active also against the Gram-negative Pseudomonas aeruginosa. The herein-obtained polyurethanes could find promising applications as antimicrobial coatings for different kinds of surfaces including medical devices, fabric for wound dressings and other textiles.
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Pyrazolo3,4-
pyrimidines represent an important class of heterocyclic compounds well-known for their anticancer activity exerted by the inhibition of eukaryotic protein kinases. Recently, ...pyrazolo3,4-
pyrimidines have become increasingly attractive for their potential antimicrobial properties. Here, we explored the activity of a library of in-house pyrazolo3,4-
pyrimidines, targeting human protein kinases, against
and
and their interaction with ampicillin and kanamycin, representing important classes of clinically used antibiotics. Our results represent a first step towards the potential application of dual active pyrazolo3,4-
pyrimidine kinase inhibitors in the prevention and treatment of bacterial infections in cancer patients.
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The enzymatically synthesized poly (glycerol adipate) (PGA) has demonstrated all the desirable key properties required from a performing biomaterial to be considered a versatile “polymeric-tool” in ...the broad field of drug delivery. The step-growth polymerization pathway catalyzed by lipase generates a highly functionalizable platform while avoiding tedious steps of protection and deprotection. Synthesis requires only minor purification steps and uses cheap and readily available reagents. The final polymeric material is biodegradable, biocompatible and intrinsically amphiphilic, with a good propensity to self-assemble into nanoparticles (NPs). The free hydroxyl group lends itself to a variety of chemical derivatizations via simple reaction pathways which alter its physico-chemical properties with a possibility to generate an endless number of possible active macromolecules. The present work aims to summarize the available literature about PGA synthesis, architecture alterations, chemical modifications and its application in drug and gene delivery as a versatile carrier. Following on from this, the evolution of the concept of enzymatically-degradable PGA-drug conjugation has been explored, reporting recent examples in the literature.
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•Low level (<1% w/w) quantification of two polymorphic forms in an intact tablet.•Measurement times <2s achievable through use of beam enhancer technology.•DoE calibration samples ...approach facilitates both API AND excipient predictions from one measurement.•Able to distinguish API degradation while excipient content remained unchanged.•Transmission Raman technology allows fast, non-destructive, bulk sampling of intact tablets.
This proof of concept study demonstrates the application of transmission Raman spectroscopy (TRS) to the non-invasive and non-destructive quantification of low levels (0.62–1.32% w/w) of an active pharmaceutical ingredient’s polymorphic forms in a pharmaceutical formulation. Partial least squares calibration models were validated with independent validation samples resulting in prediction RMSEP values of 0.03–0.05% w/w and a limit of detection of 0.1–0.2% w/w. The study further demonstrates the ability of TRS to quantify all tablet constituents in one single measurement. By analysis of degraded stability samples, sole transformation between polymorphic forms was observed while excipient levels remained constant. Additionally, a beam enhancer device was used to enhance laser coupling to the sample, which allowed comparable prediction performance at 60 times faster rates (0.2s) than in standard mode.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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(
-2-hydroxypropylmethacrylamide)-
-poly(
-(2-(methylthio)ethyl)acrylamide) (PHPMAm-
-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)
affording spheres and long chain P(HPMAm)
yielding vesicles. This further induces different responses to H
O
, with spheres fragmenting and vesicles aggregating. Folic acid (FA) is successfully conjugated to the P(HPMAm)
, which self-assembles into FA-functionalized P(HPMAm)
-
-P(MTEAM)
polymersomes. The FA-functionalized P(HPMAm)
-
-P(MTEAM)
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 H
O
. 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.
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This study aimed to improve the anticancer effect of
herbal extract (CME) on breast cancer cells with hyaluronic acid (HYA) surface-decorated lipid polymer hybrid nanoparticles (LPNPs) and evaluate ...the applicability of a synthesized poly(glycerol adipate) (PGA) polymer for LPNP preparation. Firstly, cholesterol- and vitamin E-grafted PGA polymers (PGA-CH and PGA-VE, respectively) were fabricated, with and without maleimide-ended polyethylene glycol. Subsequently, CME, which contained an active cordycepin equaling 9.89% of its weight, was encapsulated in the LPNPs. The results revealed that the synthesized polymers could be used to prepare CME-loaded LPNPs. The LPNP formulations containing Mal-PEG were decorated with cysteine-grafted HYA via thiol-maleimide reactions. The HYA-decorated PGA-based LPNPs substantially enhanced the anticancer effect of CME against MDA-MB-231 and MCF-7 breast cancer cells by enhancing cellular uptake through CD44 receptor-mediated endocytosis. This study demonstrated the successful targeted delivery of CME to the CD44 receptors of tumor cells by HYA-conjugated PGA-based LPNPs and the new application of synthesized PGA-CH- and PGA-VE-based polymers in LPNP preparation. The developed LPNPs showed promising potential for the targeted delivery of herbal extracts for cancer treatment and clear potential for translation in in vivo experiments.
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To improve the biological and toxicological properties of Mefenamic acid (MA), the galactosylated prodrug of MA named MefeGAL was included in polymeric solid dispersions (PSs) composed of ...poly(glycerol adipate) (PGA) and Pluronic® F68 (MefeGAL-PS). MefeGAL-PS was compared with polymeric solid formulations of MA (MA-PS) or a mixture of equal ratio of MefeGAL/MA (Mix-PS).
The in vitro and in vivo pharmacological and toxicological profiles of PSs have been investigated. In detail, we evaluated the anti-inflammatory (carrageenan-induced paw edema test), analgesic (acetic acid-induced writhing test) and ulcerogenic activity in mice after oral treatment. Additionally, the antiproliferative activity of PSs was assessed on in vitro models of colorectal and non-small cell lung cancer.
When the PSs were resuspended in water, MefeGAL’s, MA’s and their mixture’s apparent solubilities improved due to the interaction with the polymeric formulation. By comparing the in-vivo biological performance of MefeGAL-PS with that of MA, MefeGAL and MA-PS, it was seen that MefeGAL-PS exhibited the same sustained and delayed analgesic and anti-inflammatory profile as MefeGAL but did not cause gastrointestinal irritation. The pharmacological effect of Mix-PS was present from the first hours after administration, lasting about 44 hours with only slight gastric mucosa irritation. In-vitro evaluation indicated that Mix-PS had statistically significant higher cytotoxicity than MA-PS and MefeGAL-PS.
These preliminary data are promising evidence that the galactosylated prodrug approach in tandem with a polymer-drug solid dispersion formulation strategy could represent a new drug delivery route to improve the solubility and biological activity of NSAIDs.
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•Galactosylated prodrug and polymeric solid dispersion strategies were applied.•Combined drug delivery strategies reduced the ulcerogenicity of mefenamic acid.•By applying two approaches, the biological activity of mefenamic acid was extended.•The concomitant use of two strategies boosted the cytotoxicity of mefenamic acid.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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