Background: Meltdose tacrolimus (Envarsus (R)) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose... Show moreBackground: Meltdose tacrolimus (Envarsus (R)) has been marketed as a formulation achieving a more consistent tacrolimus exposure. Due to the narrow therapeutic window of tacrolimus, dose individualization is essential. Relaxation of the upper age limits for kidney transplantations has resulted in larger numbers of elderly patients receiving tacrolimus. However, due to the physiological changes caused by aging, the tacrolimus pharmacokinetics (PK) might be altered. The primary aim was to develop a population PK model in elderly kidney transplant recipients. Secondary aims were the development and evaluation of a limited sampling strategy (LSS) for AUC estimation. Methods: A total of 34 kidney transplant recipients aged >= 65 years, starting on meltdose tacrolimus directly after transplantation, were included. An eight-point whole blood AUC0-24h and an abbreviated dried blood spot (DBS) AUC0-24h were obtained. The PK data were analyzed using nonlinear mixed effect modeling methods. Results: The PK data were best described using a two-compartment model, including three transit compartments and a mixture model for oral absorption. The best three-sample LSS was T = 0, 2, 6 h. The best four-sample LSSs were T = 0, 2, 6, 8 h and T = 0, 1, 6, 8 h. Conclusions: The developed population PK model adequately described the tacrolimus PK data in a population of elderly kidney transplant recipients. In addition, the developed population PK model and LSS showed an adequate estimation of tacrolimus exposure, and may therefore be used to aid in tacrolimus dose individualization. Show less
Nitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT... Show moreNitrofurantoin (NFT) is a commonly used antibiotic for the treatment of urinary tract infections that can cause liver toxicity. Despite reports of hepatic adverse events associated with NFT exposure, there is still limited understanding of the interplay between NFT exposure, its disposition, and the risk of developing liver toxicity. In this study, we aim to develop a physiologically based pharmacokinetic (PBPK) model for NFT in three different species (rabbits, rats, and humans) that can be used as a standard tool for predicting drug-induced liver injury (DILI). We created several versions of the PBPK model using previously published kinetics data from rabbits, and integrated enterohepatic recirculation (EHR) using rat data. Our model showed that active tubular secretion and reabsorption in the kidney are critical in explaining the non-linear renal clearance and urine kinetics of NFT. We subsequently extrapolated the PBPK model to humans. Adapting the physiology to humans led to predictions consistent with human kinetics data, considering a low amount of NFT to be excreted into bile. Model simulations predicted that the liver of individuals with a moderate-to-severe glomerular filtration rate (GFR) is exposed to two-to-three-fold higher concentrations of NFT than individuals with a normal GFR, which coincided with a substantial reduction in the NFT urinary concentration. In conclusion, people with renal insufficiency may be at a higher risk of developing DILI due to NFT exposure, while at the same time having a suboptimal therapeutic effect with a high risk of drug resistance. Our PBPK model can in the future be used to predict NFT kinetics in individual patients on the basis of characteristics like age and GFR. Show less
Lipid nanoparticles (LNPs) have gained great attention as carriers for mRNA-based therapeutics, finding applications in various indications, extending beyond their recent use in vaccines for... Show moreLipid nanoparticles (LNPs) have gained great attention as carriers for mRNA-based therapeutics, finding applications in various indications, extending beyond their recent use in vaccines for infectious diseases. However, many aspects of LNP structure and their effects on efficacy are not well characterized. To further exploit the potential of mRNA therapeutics, better control of the relationship between LNP formulation composition with internal structure and transfection efficiency in vitro is necessary. We compared two well-established ionizable lipids, namely DODMA and MC3, in combination with two helper lipids, DOPE and DOPC, and two polymer-grafted lipids, either with polysarcosine (pSar) or polyethylene glycol (PEG). In addition to standard physicochemical characterization (size, zeta potential, RNA accessibility), small-angle X-ray scattering (SAXS) was used to analyze the structure of the LNPs. To assess biological activity, we performed transfection and cell-binding assays in human peripheral blood mononuclear cells (hPBMCs) using Thy1.1 reporter mRNA and Cy5-labeled mRNA, respectively. With the SAXS measurements, we were able to clearly reveal the effects of substituting the ionizable and helper lipid on the internal structure of the LNPs. In contrast, pSar as stealth moieties affected the LNPs in a different manner, by changing the surface morphology towards higher roughness. pSar LNPs were generally more active, where the highest transfection efficiency was achieved with the LNP formulation composition of MC3/DOPE/pSar. Our study highlights the utility of pSar for improved mRNA LNP products and the importance of pSar as a novel stealth moiety enhancing efficiency in future LNP formulation development. SAXS can provide valuable information for the rational development of such novel formulations by elucidating structural features in different LNP compositions. Show less
Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although... Show moreMycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF's active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-& gamma; production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression. Show less
Veld, A.E. in 't; Jansen, M.A.A.; Kam, M.L. de; Yavuz, Y.; Moes, D.J.A.R.; Oudhoff, K. A.; ... ; Moerland, M. 2023
Mycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although... Show moreMycophenolate mofetil (MMF) is part of the standard immunosuppressive treatment after transplantation and usually given as "one-dose-fits-all" together with a calcineurin inhibitor (CNI). Although drug concentrations are frequently monitored, there is still a group of patients who experience side effects related to excessive or insufficient immune suppression. We therefore aimed to identify biomarkers that reflect the overall immune status of the patient and might support individualized dosing. We previously studied immune biomarkers for CNIs and aimed to investigate whether these are also suitable to monitor MMF activity. Healthy volunteers received a single dose of MMF or placebo, after which IMPDH enzymatic activity, T cell proliferation, and cytokine production were measured and compared to MPA (MMF's active metabolite) concentration in three different matrices (plasma, peripheral blood mononuclear cells, and T cells). MPA concentrations in T cells exceeded those in PBMCs, but all intracellular concentrations correlated strongly with plasma concentrations. At clinically relevant MPA concentrations, IL-2 and IFN-γ production was mildly suppressed, while MPA T cell proliferation was strongly inhibited. Based on these data, it is expected that monitoring of T cell proliferation in MMF-treated transplantation patients may be a valid strategy to avoid excessive immune suppression. Show less
Fu, Y.; Snelder, N.; Guo, T.; Graaf, P.H. van der; Hasselt, J.G.C. van 2023
Early prediction, quantification and translation of cardiovascular hemodynamic drug effects is essential in pre-clinical drug development. In this study, a novel hemodynamic cardiovascular systems ... Show moreEarly prediction, quantification and translation of cardiovascular hemodynamic drug effects is essential in pre-clinical drug development. In this study, a novel hemodynamic cardiovascular systems (CVS) model was developed to support these goals. The model consisted of distinct system- and drug-specific parameter, and uses data for heart rate (HR), cardiac output (CO), and mean atrial pressure (MAP) to infer drug mode-of-action (MoA). To support further application of this model in drug development, we conducted a systematic analysis of the estimation performance of the CVS model to infer drug- and system-specific parameters. Specifically, we focused on the impact on model estimation performance when considering differences in available readouts and the impact of study design choices. To this end, a practical identifiability analysis was performed, evaluating model estimation performance for different combinations of hemodynamic endpoints, drug effect sizes, and study design characteristics. The practical identifiability analysis showed that MoA of drug effect could be identified for different drug effect magnitudes and both system- and drug-specific parameters can be estimated precisely with minimal bias. Study designs which exclude measurement of CO or use a reduced measurement duration still allow the identification and quantification of MoA with acceptable performance. In conclusion, the CVS model can be used to support the design and inference of MoA in pre-clinical CVS experiments, with a future potential for applying the uniquely identifiable systems parameters to support inter-species scaling. Show less
Despite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking.... Show moreDespite the numerous therapeutic options to treat bleeding or thrombosis, a comprehensive quantitative mechanistic understanding of the effects of these and potential novel therapies is lacking. Recently, the quality of quantitative systems pharmacology (QSP) models of the coagulation cascade has improved, simulating the interactions between proteases, cofactors, regulators, fibrin, and therapeutic responses under different clinical scenarios. We aim to review the literature on QSP models to assess the unique capabilities and reusability of these models. We systematically searched the literature and BioModels database reviewing systems biology (SB) and QSP models. The purpose and scope of most of these models are redundant with only two SB models serving as the basis for QSP models. Primarily three QSP models have a comprehensive scope and are systematically linked between SB and more recent QSP models. The biological scope of recent QSP models has expanded to enable simulations of previously unexplainable clotting events and the drug effects for treating bleeding or thrombosis. Overall, the field of coagulation appears to suffer from unclear connections between models and irreproducible code as previously reported. The reusability of future QSP models can improve by adopting model equations from validated QSP models, clearly documenting the purpose and modifications, and sharing reproducible code. The capabilities of future QSP models can improve from more rigorous validation by capturing a broader range of responses to therapies from individual patient measurements and integrating blood flow and platelet dynamics to closely represent in vivo bleeding or thrombosis risk. Show less
Gent, M.E. van; Baaren, T. van; Klodzinska, S.N.; Ali, M.; Dolezal, N.; Doodewaerd, B.R. van; ... ; Nibbering, P.H. 2023
Chronic wound infections colonized by bacteria are becoming more difficult to treat with current antibiotics due to the development of antimicrobial resistance (AMR) as well as biofilm and... Show moreChronic wound infections colonized by bacteria are becoming more difficult to treat with current antibiotics due to the development of antimicrobial resistance (AMR) as well as biofilm and persister cell formation. Synthetic antibacterial and antibiofilm peptide (SAAP)-148 is an excellent alternative for treatment of such infections but suffers from limitations related to its cationic peptidic nature and thus instability and possible cytotoxicity, resulting in a narrow therapeutic window. Here, we evaluated SAAP-148 encapsulation in nanogels composed of octenyl succinic anhydride (OSA)-modified hyaluronic acid (HA) to circumvent these limitations. SAAP-148 was efficiently (>98%) encapsulated with high drug loading (23%), resulting in monodispersed anionic OSA-HA nanogels with sizes ranging 204–253 nm. Nanogel lyophilization in presence of polyvinyl alcohol maintained their sizes and morphology. SAAP-148 was sustainedly released from lyophilized nanogels (37–41% in 72 h) upon reconstitution. Lyophilized SAAP-148-loaded nanogels showed similar antimicrobial activity as SAAP-148 against planktonic and biofilm-residing AMR Staphylococcus aureus and Acinetobacter baumannii. Importantly, formulated SAAP-148 showed reduced cytotoxicity against human erythrocytes, primary human skin fibroblasts and human keratinocytes. Additionally, lyophilized SAAP-148-loaded nanogels eradicated AMR S. aureus and A. baumannii colonizing a 3D human epidermal model, without inducing any cytotoxicity in contrast to SAAP-148. These findings indicate that OSA-HA nanogels increase SAAP-148′s therapeutic potential for treatment of skin wound infections. Show less
Here, we describe the synthesis of a novel type of rare-earth-doped nanoparticles (NPs) for multimodal imaging, by combining the rare-earth elements Ce, Gd and Nd in a crystalline host lattice... Show moreHere, we describe the synthesis of a novel type of rare-earth-doped nanoparticles (NPs) for multimodal imaging, by combining the rare-earth elements Ce, Gd and Nd in a crystalline host lattice consisting of CaF2 (CaF2: Ce, Gd, Nd). CaF2: Ce, Gd, Nd NPs are small (15-20 nm), of uniform shape and size distribution, and show good biocompatibility and low immunogenicity in vitro. In addition, CaF2: Ce, Gd, Nd NPs possess excellent optical properties. CaF2: Ce, Gd, Nd NPs produce downconversion emissions in the second near-infrared window (NIR-II, 1000-1700 nm) under 808 nm excitation, with a strong emission peak at 1056 nm. Excitation in the first near- infrared window (NIR-I, 700-900 nm) has the advantage of deeper tissue penetration power and reduced autofluorescence, compared to visible light. Thus, CaF2: Ce, Gd, Nd NPs are ideally suited for in vivo fluorescence imaging. In addition, the presence of Gd3+ makes the NPs intrinsically monitorable by magnetic resonance imaging (MRI). Moreover, next to fluorescence and MR imaging, our results show that CaF2: Ce, Gd, Nd NPs can be used as imaging probes for photoacoustic imaging (PAI) in vitro. Therefore, due to their biocompatibility and suitability as multimodal imaging probes, CaF2: Ce, Gd, Nd NPs exhibit great potential as a traceable imaging agent in biomedical applications. Show less
Oliveira, A.L.C.D.L.; Schomann, T.; Geus-Oei, L.F. de; Kapiteijn, E.; Cruz, L.J.; Araujo, R.F. de 2022
Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has... Show moreTherapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose-effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment. Show less
Veld, A.E.I. 't; Jansen, M.A.A.; Huisman, B.W.; Schoonakker, M.; Kam, M.L. de; Moes, D.J.A.R.; ... ; Moerland, M. 2022
Therapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has... Show moreTherapeutic drug monitoring (TDM) of calcineurin inhibitors (i.e., tacrolimus and cyclosporin A) is standard of care after solid organ transplantation. Although the incidence of acute rejection has strongly decreased, there are still many patients who experience severe side effects or rejection after long-term treatment. In this healthy volunteer study we therefore aimed to identify biomarkers to move from a pharmacokinetic-based towards a pharmacodynamic-based monitoring approach for calcineurin inhibitor treatment. Healthy volunteers received a single dose of cyclosporine A (CsA) or placebo, after which whole blood samples were stimulated to measure ex vivo T cell functionality, including proliferation, cytokine production, and activation marker expression. The highest whole blood concentration of CsA was found at 2 h post-dose, which resulted in a strong inhibition of interferon gamma (IFNy) and interleukin-2 (IL-2) production and expression of CD154 and CD71 on T cells. Moreover, the in vitro effect of CsA was studied by incubation of pre-dose whole blood samples with a concentration range of CsA. The average in vitro and ex vivo CsA activity overlapped, making the in vitro dose-effect relationship an interesting method for prediction of post-dose drug effect. The clinical relevance of the results is to be explored in transplantation patients on calcineurin inhibitor treatment. Show less
The bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study,... Show moreThe bidirectional pulsatile movement of cerebrospinal fluid (CSF), instead of the traditionally believed unidirectional and constant CSF circulation, has been demonstrated. In the present study, the structure and parameters of the CSF compartments were revisited in our comprehensive and validated central nervous system (CNS)-specific, physiologically based pharmacokinetic (PBPK) model of healthy rats (LeiCNS-PK3.0). The bidirectional and site-dependent CSF movement was incorporated into LeiCNS-PK3.0 to create the new LeiCNS-PK"3.1" model. The physiological CSF movement rates in healthy rats that are unavailable from the literature were estimated by fitting the PK data of sucrose, a CSF flow marker, after intra-CSF administration. The capability of LeiCNS-PK3.1 to describe the PK profiles of other molecules was compared with that of the original LeiCNS-PK3.0 model. LeiCNS-PK3.1 demonstrated superior description of the CSF PK profiles of a range of small molecules after intra-CSF administration over LeiCNS-PK3.0. LeiCNS-PK3.1 also retained the same level of predictability of CSF PK profiles in cisterna magna after intravenous administration. These results support the theory of bidirectional and site-dependent CSF movement across the entire CSF space over unidirectional and constant CSF circulation in healthy rats, pointing out the need to revisit the structures and parameters of CSF compartments in CNS-PBPK models. Show less
Immune checkpoint blocking therapy is a promising cancer treatment modality, though it has limitations such as systemic toxicity, which can often be traced to uncontrolled antibody spread.... Show moreImmune checkpoint blocking therapy is a promising cancer treatment modality, though it has limitations such as systemic toxicity, which can often be traced to uncontrolled antibody spread. Controlling antibody release with delivery systems is, therefore, an attractive approach to reduce systemic antibody spread and potentially mitigate the side effects of checkpoint immunotherapy. Here, bacterial cellulose (BC) was produced and investigated as a delivery system for optimizing checkpoint-blocking antibody delivery. BC was produced in 24-well plates, and afterward, the edges were removed to obtain square-shaped BC samples with a surface of similar to 49 mm(2). This customization was necessary to allow smooth in vivo implantation. Scanning electron microscopy revealed the dense cellulose network within BC. Human IgG antibody was included as the model antibody for loading and release studies. IgG antibody solution was injected into the center of BC samples. In vitro, all IgG was released within 24 to 48 h. Cell culture experiments demonstrated that BC neither exerted cytotoxic effects nor induced dendritic cell activation. Antibody binding assays demonstrated that BC does not hamper antibody function. Finally, antibody-loaded BC was implanted in mice, and serum measurements revealed that BC significantly reduced IgG and anti-CTLA-4 spread in mice. BC implantation did not induce side effects in mice. Altogether, BC is a promising and safe delivery system for optimizing the delivery and release of checkpoint-blocking antibodies. Show less
Jorquera-Cordero, C.; Lara, P.; Cruz, L.J.; Schomann, T.; Hofslot, A. van; Carvalho, T.G. de; ... ; Araujo, R.F. de 2022
One of the main reasons for cancer's low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate... Show moreOne of the main reasons for cancer's low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the beta-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-kappa B was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-beta. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer. Show less
Nowadays, cancer poses a significant hazard to humans. Limitations in early diagnosis techniques not only result in a waste of healthcare resources but can even lead to delays in diagnosis and... Show moreNowadays, cancer poses a significant hazard to humans. Limitations in early diagnosis techniques not only result in a waste of healthcare resources but can even lead to delays in diagnosis and treatment, consequently reducing cure rates. Therefore, it is crucial to develop an imaging probe that can provide diagnostic information precisely and rapidly. Here, we used a simple hydrothermal method to design a multimodal imaging probe based on the excellent properties of rare-earth ions. Calcium fluoride co-doped with ytterbium, gadolinium, and neodymium (CaF2:Y,Gd,Nd) nanoparticles (NPs) is highly crystalline, homogeneous in morphology, and displays a high biosafety profile. In addition, in vitro and ex vivo experiments explored the multimodal imaging capability of CaF2:Y,Gd,Nd and demonstrated the efficient performance of CaF2:Y,Gd,Nd during NIR-II fluorescence/photoacoustic/magnetic resonance imaging. Collectively, our novel diagnosis nanoparticle will generate new ideas for the development of multifunctional nanoplatforms for disease diagnosis and treatment. Show less
Cartilage diseases currently affect a high percentage of the world's population. Almost all of these diseases, such as osteoarthritis (OA), cause inflammation of this soft tissue. However, this... Show moreCartilage diseases currently affect a high percentage of the world's population. Almost all of these diseases, such as osteoarthritis (OA), cause inflammation of this soft tissue. However, this could be controlled with biomaterials that act as an anti-inflammatory delivery system, capable of dosing these drugs over time in a specific area. The objective of this study was to incorporate etanercept (ETA) into porous three-layer scaffolds to decrease the inflammatory process in this soft tissue. ETA is a blocker of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). For this reason, the scaffold was built based on natural polymers, including chitosan and type I collagen. The scaffold was grafted next to subchondral bone using hydroxyapatite as filler. One of the biomaterials obtained was also crosslinked to compare its mechanical properties with the non-treated one. Both samples' physicochemical properties were studied with SEM, micro-CT and photoacoustic imaging, and their rheological properties were also compared. The cell viability and proliferation of the human chondrocyte C28/I2 cell line were studied in vitro. An in vitro and in vivo controlled release study was evaluated in both specimens. The ETA anti-inflammatory effect was also studied by in vitro TNF-alpha and IL-6 production. The crosslinked and non-treated scaffolds had rheological properties suitable for this application. They were non-cytotoxic and favoured the in vitro growth of chondrocytes. The in vitro and in vivo ETA release showed desirable results for a drug delivery system. The TNF-alpha and IL-6 production assay showed that this drug was effective as an anti-inflammatory agent. In an in vivo OA mice model, safranin-O and fast green staining was carried out. The OA cartilage tissue improved when the scaffold with ETA was grafted in the damaged area. These results demonstrate that this type of biomaterial has high potential for clinical applications in tissue engineering and as a controlled drug delivery system in OA articular cartilage. Show less
3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation... Show more3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation of these innovative drug products. Extensive research has been conducted on the compliance of 3D-printed drug products to a pediatric quality target product profile. The 3D-printed tablets were of particular interest in providing superior dosing and release profile similarity compared to conventional drug manipulation and compounding methods, such as oral liquids. In the future, acceptance of 3D-printed tablets in the pediatric patient population might be better than current treatments due to improved palatability. Further research should focus on expanding clinical knowledge, providing regulatory guidance and expansion of the product range, including dosage form possibilities. Moreover, it should enable the use of diverse good manufacturing practice (GMP)-ready 3D printing techniques for the production of various drug products for the pediatric patient population. Show less
Photodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors... Show morePhotodynamic therapy (PDT), in which a light source is used in combination with a photosensitizer to induce local cell death, has shown great promise in therapeutically targeting primary tumors with negligible toxicity and minimal invasiveness. However, numerous studies have shown that noninvasive PDT alone is not sufficient to completely ablate tumors in deep tissues, due to its inherent shortcomings. Therefore, depending on the characteristics and type of tumor, PDT can be combined with surgery, radiotherapy, immunomodulators, chemotherapy, and/or targeted therapy, preferably in a patient-tailored manner. Nanoparticles are attractive delivery vehicles that can overcome the shortcomings of traditional photosensitizers, as well as enable the codelivery of multiple therapeutic drugs in a spatiotemporally controlled manner. Nanotechnology-based combination strategies have provided inspiration to improve the anticancer effects of PDT. Here, we briefly introduce the mechanism of PDT and summarize the photosensitizers that have been tested preclinically for various cancer types and clinically approved for cancer treatment. Moreover, we discuss the current challenges facing the combination of PDT and multiple cancer treatment options, and we highlight the opportunities of nanoparticle-based PDT in cancer therapies. Show less
