Search Results (9)

Background: Retrospective studies are often criticized for their susceptibility to case selection bias compared to prospective studies, which include all patients consecutively and are thus less prone to such limitations. However, the larger sample sizes typical of retrospective studies can sometimes offset this drawback. On behalf of the Fondazione Italiana Linfomi (FIL), a substantial retrospective study involving 946 patients was conducted to examine the use of non-pegylated liposomal anthracycline (Myocet). This was followed by a prospective study, the Prospective Elderly Project, which enrolled 308 patients treated with the same liposomal anthracycline regimen. Methods: The objective of this analysis was to determine whether the patient cohort from the retrospective study significantly differed from the cohort in the prospective study. Statistical hypothesis testing was applied to assess whether the samples from both studies originated from the same underlying population. The Anderson–Darling test, a non-parametric statistical method, was utilized to evaluate and compare the overall survival distributions between the two patient cohorts. Results: The statistical tests produced conflicting results, suggesting a potential selection bias in the retrospective study or the possibility that the two groups were from the same population. These discrepancies may have arisen due to the choice of statistical methods or the quality of the data analyzed. Conclusions: This study highlights the challenges of comparing retrospective and prospective cohorts and underscores the importance of selecting appropriate statistical methodologies. The findings provide valuable insights and lay the groundwork for developing innovative approaches to improve such comparisons in future research. Full article

Lipid-based nanocarriers have emerged as helpful tools to deliver sensible biomolecules such as proteins and oligonucleotides. To have a fast and robust microfluidic-based nanoparticle synthesis method, the setup of versatile equipment should allow for the rapid transfer to scale cost-effectively while ensuring tunable, precise and reproducible nanoparticle attributes. The present work aims to assess the effect of different micromixer geometries on the manufacturing of lipid nanocarriers taking into account the influence on the mixing efficiency by changing the fluid–fluid interface and indeed the mass transfer. Since the geometry of the adopted micromixer varies from those already published, a Design of Experiment (DoE) was necessary to identify the operating (total flow, flow rate ratio) and formulation (lipid concentration, lipid molar ratios) parameters affecting the nanocarrier quality. The suitable application of the platform was investigated by producing neutral, stealth and cationic liposomes, using DaunoXome^®, Myocet^®, Onivyde^® and Onpattro^® as the benchmark. The effect of condensing lipid (DOTAP, 3–10–20 mol%), coating lipids (DSPE-PEG550 and DSPE-PEG2000), as well as structural lipids (DSPC, eggPC) was pointed out. A very satisfactory encapsulation efficiency, always higher than 70%, was successfully obtained for model biomolecules (myoglobin, short and long nucleic acids). Full article

Despite the widespread use of doxorubicin (DOX) as a chemotherapeutic agent, its severe cumulative cardiotoxicity represents a significant limitation. While the liposomal encapsulation of doxorubicin (Myocet, MYO) reduces cardiotoxicity, it is crucial to understand the molecular background of doxorubicin-induced cardiotoxicity. Here, we examined circular RNA expression in a translational model of pigs treated with either DOX or MYO and its potential impact on the global gene expression pattern in the myocardium. This study furthers our knowledge about the regulatory network of circRNA/miRNA/mRNA and its interaction with chemotherapeutics. Domestic pigs were treated with three cycles of anthracycline drugs (DOX, n = 5; MYO, n = 5) to induce cardiotoxicity. Untreated animals served as controls (control, n = 3). We applied a bulk mRNA-seq approach and the CIRIquant algorithm to identify circRNAs. The most differentially regulated circRNAs were validated under cell culture conditions, following forecasting of the circRNA–miRNA–mRNA network. We identified eight novel significantly regulated circRNAs from exonic and mitochondrial regions in the porcine myocardium. The forecasted circRNA–miRNA–mRNA network suggested candidate circRNAs that sponge miR-17, miR-15b, miR-130b, the let-7 family, and miR125, together with their mRNA targets. The identified circRNA–miRNA–mRNA network provides an updated, coherent view of the mechanisms involved in anthracycline-induced cardiotoxicity. Full article

Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand–foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m²) on day 1 along with ifosfamide (3000 mg/m² on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29–0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73—0.90), while only 16% (95% CI: 0.08–0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity. Full article

We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet^®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF. Full article

Doxorubicin (DOX) is a potent anti-cancer agent that has garnered great interest in research due to its high efficacy despite dose-limiting toxicities. Several strategies have been exploited to enhance the efficacy and safety profile of DOX. Liposomes are the most established approach. Despite the improvement in safety properties of liposomal encapsulated DOX (in Doxil and Myocet), the efficacy is not superior to conventional DOX. Functionalized (targeted) liposomes present a more effective system to deliver DOX to the tumor. Moreover, encapsulation of DOX in pH-sensitive liposomes (PSLs) or thermo-sensitive liposomes (TSLs) combined with local heating has improved DOX accumulation in the tumor. Lyso-thermosensitive liposomal DOX (LTLD), MM-302, and C225-immunoliposomal(IL)-DOX have reached clinical trials. Further functionalized PEGylated liposomal DOX (PLD), TSLs, and PSLs have been developed and evaluated in preclinical models. Most of these formulations improved the anti-tumor activity compared to the currently available liposomal DOX. However, the fast clearance, the optimization of ligand density, stability, and release rate need more investigations. Therefore, we reviewed the latest approaches applied to deliver DOX more efficiently to the tumor, preserving the benefits obtained from FDA-approved liposomes. Full article

Doxorubicin (Dox) is a widely known chemotherapeutic drug that has been encapsulated into liposomes for clinical use, such as Doxil^® and Myocet^®. Both of these are prepared via remote loading methods, which require multistep procedures. Additionally, their antitumor efficacy is hindered due to the poor drug release from PEGylated liposomes in the tumor microenvironment. In this study, we aimed to develop doxorubicin-loaded lipid-based nanocarriers (LNC-Dox) based on electrostatic interaction using microfluidic technology. The resulting LNC-Dox showed high loading capacity, with a drug-to-lipid ratio (D/L ratio) greater than 0.2, and high efficacy of drug release in an acidic environment. Different lipid compositions were selected based on critical packing parameters and further studied to outline their effects on the physicochemical characteristics of LNC-Dox. Design of experiments was implemented for formulation optimization. The optimized LNC-Dox showed preferred release in acidic environments and better therapeutic efficacy compared to PEGylated liposomal Dox in vivo. Thus, this study provides a feasible approach to efficiently encapsulate doxorubicin into lipid-based nanocarriers fabricated by microfluidic rapid mixing. Full article

Liposomes are considered one of the most successful drug delivery systems (DDS) given their established utility and success in the clinic. In the past 40–50 years, Canadian scientists have made ground-breaking discoveries, many of which were successfully translated to the clinic, leading to the formation of biotech companies, the creation of research tools, such as the Lipex Extruder and the NanoAssemblr™, as well as contributing significantly to the development of pharmaceutical products, such as Abelcet^®, MyoCet^®, Marqibo^®, Vyxeos^®, and Onpattro™, which are making positive impacts on patients’ health. This review highlights the Canadian contribution to the development of these and other important liposomal technologies that have touched patients. In this review, we try to address the question of what drives innovation: Is it the individual, the teams, the funding, and/or an entrepreneurial spirit that leads to success? From this perspective, it is possible to define how innovation will translate to meaningful commercial ventures and products with impact in the future. We begin with a brief history followed by descriptions of drug delivery technologies influenced by Canadian researchers. We will discuss recent advances in liposomal technologies, including the Metaplex technology from the author’s lab. The latter exemplifies how a nanotechnology platform can be designed based on multidisciplinary groups with expertise in coordination chemistry, nanomedicines, disease, and business to create new therapeutics that can effect better outcomes in patient populations. We conclude that the team is central to the effort; arguing if the team is entrepreneurial and well positioned, the funds needed will be found, but likely not solely in Canada. Full article

Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin (“Apodox” and “lip-8-dox”) and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC₅₀) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC₅₀ = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC₅₀ was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP. Full article