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Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention., (Copyright © 2024 Cold Spring Harbor Laboratory Press; all rights reserved.)

Peptide (insulin) loaded nanoparticles (NPs) have been embedded into buccal chitosan films (Ch-films-NPs). These films were produced by solvent casting and involved incorporating in chitosan gel (1.25% w/v), NPs-Insulin suspensions at three different concentrations (1, 3, and 5mg of NPs per film) using glycerol as plasticiser. Film swelling and mucoadhesion were investigated using 0.01M PBS at 37°C and texture analyzer, respectively. Formulations containing 3mg of NPs per film produced optimised films with excellent mucoadhesion and swelling properties. Dynamic laser scattering measurements showed that the erosion of the chitosan backbone controlled the release of NPs from the films, preceding in vitro drug (insulin) release from Ch-films-NPs after 6h. Modulated release was observed with 70% of encapsulated insulin released after 360h. The use of chitosan films yielded a 1.8-fold enhancement of ex vivo insulin permeation via EpiOral™ buccal tissue construct relative to the pure drug. Flux and apparent permeation coefficient of 0.1μg/cm(2)/h and 4×10(-2)cm(2)/h were respectively obtained for insulin released from Ch-films-NPs-3. Circular dichroism and FTIR spectroscopy demonstrated that the conformational structure of the model peptide drug (insulin) released from Ch-films-NPs was preserved during the formulation process., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Mucoadhesive chitosan based films, incorporated with insulin loaded nanoparticles (NPs) made of poly(ethylene glycol)methyl ether-block-polylactide (PEG-b-PLA) have been developed and characterised. Blank-NPs were prepared by double emulsion solvent evaporation technique with varying concentrations of the copolymer (5 and 10%, w/v). The optimised formulation was loaded with insulin (model protein) at initial loadings of 2, 5 and 10% with respect to copolymer weight. The developed NPs were analysed for size, size distribution, surface charge, morphology, encapsulation efficiency and drug release. NPs showing negative (ζ)-potential (<-6 mV) with average diameter> 300 nm and a polydispersity index (P.I.) of ≈ 0.2, irrespective of formulation process, were achieved. Insulin encapsulation efficiencies of 70% and 30% for NPs-Insulin-2 and NPs-Insulin-5 were obtained, respectively. The in vitro release behaviour of both formulations showed a classic biphasic sustained release of protein over 5 weeks which was influenced by pH of the release medium. Optimised chitosan films embedded with 3mg of insulin loaded NPs were produced by solvent casting with homogeneous distribution of NPs in the mucoadhesive matrix, which displayed excellent physico-mechanical properties. The drug delivery system has been designed as a novel platform for potential buccal delivery of macromolecules., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A specific and promising approach to limit inflammation and mucin iperproduction in chronic lung diseases relies on specific inhibition of nuclear Factor-κB (NF-κB) by a decoy oligonucleotide (dec-ODN). To fulfill the requirements dictated by translation of dec-ODN therapy in humans, inhalable dry powders were designed on a rational basis to provide drug protection, sustained release and to optimize pharmacological response. To this end, large porous particles (LPP) for dec-ODN delivery made of a sustained release biomaterial (poly(lactic-co-glycolic) acid, PLGA) and an "adjuvant" hydrophilic polymer (polyethylenimine, PEI) were developed and their effects on LPS-stimulated human airway epithelial cells evaluated. The composite PLGA/PEI particles containing dec-ODN (i.e., LPP(PEI)) were successfully engineered for widespread deposition in the lung and prolonged release of intact dec-ODN in vitro. LPP(PEI) caused a prolonged inhibition of IL-8 and MUC2 expression in CF human bronchial epithelial cells and human epithelial pulmonary NCI-H292 cells, respectively, as compared to naked dec-ODN. Nonetheless, as compared to previously developed LPP, the presence of PEI was essential to construct a dec-ODN delivery system able to act in mucoepidermoid lung epithelial cells. In perspective, engineering LPP with PEI may become a key factor for tuning carrier properties, controlling lung inflammation and mucin production which, in turn, can foster in vivo translation of dec-ODN therapy.

The development of a novel generation of drug-eluting stent (DES) relies upon the idea to obtain very flexible platforms able to overcome some issues associated to available devices and widen their field of application, especially to the currently emerging biotech therapeutics. Here, we propose a new concept of DES named microsphere-integrated drug-eluting stent (MIDES) composed of drug eluting biodegradable poly(D,L-lactide-co-glycolide) microspheres--encapsulating an hydrophilic model molecule (dextran)--fully integrated in a poly(2-hydroxy-ethyl-methacrylate) coating. By implementing a modified spray-coating technique, we have been able to achieve a thin (10 μm), smooth, and homogeneous hydrogel surface embedding underneath a population of two different microparticles formulations--Dex502H and Dex506. The amount of drug can be tailored, resulting in a dextran loading as high as 1.4 μg/cm, by simply reiteration of coating layer deposition making the MIDES a custom-made device where the release kinetics can be further modified by opportunely choosing microsphere properties. DES use is nowadays restricted to delivery of hydrophobic pharmaceuticals; release of hydrophilic therapeutics from MIDES can, however, be finely controlled by specifically engineering biodegradable microspheres. By varying polymer resomer, we obtained a tunable release rate in the first month of delivery. Depending on the microspheres properties release profile changes drastically moving from a biphasic release, in the case of Dex502H, with a burst of about 20% in the first day to a more sustained release for Dex506 particles. As proof of principle, we also demonstrated that MIDES approach can allows the delivery of two different agents opening up the way to a multitherapy in restenosis treatment., (Copyright © 2011 Wiley Periodicals, Inc.)

Background: Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Neutrophil-dominated inflammation and chronic bacterial infection are still considered the primary cause of bronchioectasis, respiratory failure and consequent death in CF patients. Activation of nuclear factor (NF)-κB is responsible for overproduction of cytokines, such as interleukin (IL)-6 and IL-8, in airways of CF patients. Thus, decoy oligodeoxynucleotides against NF-κB (dec-ODN) may limit lung inflammation in CF. In the present study, we studied the effects of dec-ODN delivered through biodegradable and respirable poly(D,L-lactide-co-glycolide) large porous particles (LPP) on IL-6 and IL-8 mRNA expression as well as NF-κB/DNA binding activity in cystic fibrosis cells stimulated with lipopolysaccharide (LPS) from Pseudomonas aeruginosa., Methods: dec-ODN LPP were prepared by a modified double emulsion technique and characterized in terms of size, morphology, tapped density and dec-ODN loading. Human epithelial bronchial IB3-1 (CFTR-mutated) as well as S9 (CFTR-corrected) were stimulated with LPS from P. aeruginosa for 24 and 72 h in the absence or presence of naked dec-ODN or dec-ODN LPP., Results: Stimulation of cells with LPS from P. aeruginosa caused an increase of IL-6 and IL-8 mRNA levels, which were significantly inhibited by dec-ODN LPP at 24 and 72 h, whereas naked dec-ODN inhibited those only at 24 h. Similar effects were exhibited by dec-ODN LPP or naked dec-ODN on NF-κB/DNA binding activity., Conclusions: Our observations indicate that respirable biodegradable dec-ODN LPP may represent a promising strategy for inhibiting NF-κB transcriptional activity and related gene expression and, thus, reduce lung chronic inflammation in CF patients., (Copyright © 2011 John Wiley & Sons, Ltd.)

The chemical conversion of simvastatin from the lactone (SVL) to the hydroxyacid (SVA) form is becoming an intriguing issue associated with the pharmacological use of SVL. On this matter, recent findings suggest that SVL complexation with cyclodextrins (CDs) may be a useful strategy to affect its aqueous solubility and chemical stability. In this work, a reverse-phase high-performance liquid chromatography (RP-HPLC) method able to selectively identify and quantify SVL and SVA has been set up, validated and applied to follow SVL hydrolysis in the presence of HPβCD. The combination of stability results with simvastatin/HPβCD stability constants achieved from UV-vis measurements and solubility/dissolution studies allowed to get an insight into SVL/HPβCD, SVA/HPβCD and SVL/SVA equilibria taking place in aqueous solution. Results show that in the presence of HPβCD the aqueous SVL/SVA equilibrium is shifted versus the hydroxyacid form. UV-vis results, showing that the lactone and the open-ring form of simvastatin interact with HPβCD in a similar extent, suggest that hydrolysis occurs also on SVL/HPβCD complex, thus supporting a mode of interaction that does not involve the lactone ring. This hypothesis is strengthened by NMR analysis performed on SVA, HPβCD and their inclusion complex, which indicates that the lactone ring is not included in HPβCD hydrophobic cavity. Finally, results suggest that particular attention must be paid to SVL lactonization in aqueous solution when using CD-based formulations and in demonstrating their effective benefit for a specific therapeutic use., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Gas-foamed large porous particles (gfLPP) based on poly(lactic-co-glycolic) acid (PLGA) have been recently suggested as potential carriers for pulmonary drug delivery. In this work, we attempt to engineer gfLPP for efficient local delivery of macromolecules in the lungs. Particles were fabricated by the double emulsion-solvent evaporation technique using ammonium bicarbonate as porogen. To improve particle technological properties, two lipid aid excipients, namely dipalmitoylphosphatidylcholine (DPPC) and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), were tested. Preliminary technological studies performed on unloaded gfLPP showed that the addition of an appropriate amount of NH(4)(HCO(3)), which spontaneously produces CO(2) and NH(3) during solvent evaporation, is essential to achieve a homogeneous population of highly porous particles with optimal aerodynamic properties. Then, the effect of the presence of DPPC or DOTAP upon the properties of gfLPP containing a model hydrophilic macromolecule, rhodamine B isothiocyanate-dextran (Rhod-dex), was assessed. We found that in the case of hydrophilic macromolecules unable to interact with PLGA end-groups, such as Rhod-dex, excipient addition is essential to increase the amount of drug entrapped within gfLPP, being as high as 80% only for DPPC- or DOTAP-engineered gfLPP. Also Rhod-dex release profile from gfLPP was strongly affected by excipient addition in the initial formulation, with lipid-engineered gfLPP allowing for a more prolonged release of Rhod-dex as compared to excipient-free gfLPP. A further modulation of Rhod-dex initial release rate could be achieved when DOTAP was used, likely due to the electrostatic interactions occurring between macromolecule and cationic phospholipid. Conceiving the developed gfLPP for drug inhalation, DPPC- and DOTAP-engineered gfLPP displayed optimal MMAD(exp) values falling within the range 6.1-7.6 microm and very low geometric standard deviations (GSD) varying between 1.2 and 1.3. In vivo deposition studies performed after intra-tracheal administration of gfLPP in rats confirmed the ability of the developed dry powders to deposit along bronchia and bronchioles. In perspective, lipid-engineered gfLPP represent a viable alternative to LPP developed so far to achieve local and prolonged release of hydrophilic macromolecules, such as nucleic acids, in the lungs., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

The aim of the present work is to develop large porous particles (LPP) of poly (lactide-co-glycolide) (PLGA) containing insulin with optimal aerodynamic properties and to test their in vivo potential, in pulmonary delivery. Insulin-loaded LPP were fabricated by a double emulsion method by aid of hydroxypropyl-beta-cyclodextrin (HPbetaCD). Conceiving this system for the controlled release of insulin to the lungs, the aerosolization properties and the release features in simulated lung fluids of PLGA/HPbetaCD/insulin LPP were investigated in depth. The technological results show that the combination of appropriate amounts of insulin and HPbetaCD plays a crucial role to achieve PLGA/HPbetaCD/insulin LPP with the desired bulk and aerodynamic properties, that is a highly porous structure, a very low density (0.1 g/ml), an experimental mass mean aerodynamic diameter (MMAD(exp)) ranging from 4.01 to 7.00 and a fine particle fraction (FPF) estimated to be 26.9-89.6% at the different airflow rates tested (i.e. 30-90 l/min). Confocal microscopy studies, performed after administration of labeled PLGA/HPbetaCD/insulin LPP to the rat lung by means of a low-scale dry powder inhaler (DPI), suggest that particles reach alveoli and remain in situ after delivery. The pharmacological effect of PLGA/HPbetaCD/insulin LPP was confirmed by dose-response studies performed on both normoglycaemic and streptozotocin-induced diabetic rats. While insulin solutions administered via pulmonary route are unable to cause a significant hypoglycaemic effect, insulin delivered through PLGA/HPbetaCD/insulin LPP at the same doses (0.5-4.0 IU/kg) significantly reduces blood glucose level as a function of the administered dose in both animal models. The developed LPP, tested in hyperglycaemic rats at evident pathological conditions, exerts a very significant and longer hypoglycaemic effect even at insulin doses as low as 0.5 IU/kg (about 0.5 mg of PLGA/HPbetaCD/insulin LPP per rat) as compared to a insulin solution. Taken together, our results support the viability of a dry powder formulation based on biodegradable LPP for the controlled release of insulin to the lungs. In vivo data show that PLGA/HPbetaCD/insulin LPP are able to reach alveoli, release insulin, which is absorbed in its bioactive form.