Elucidating the Influence of Tumor Presence on the Polymersome Circulation Time in Mice

The use of nanoparticles as tumor-targeting agents is steadily increasing, and the influence of nanoparticle characteristics such as size and stealthiness have been established for a large number of nanocarrier systems. However, not much is known about the impact of tumor presence on nanocarrier circulation times. This paper reports on the influence of tumor presence on the in vivo circulation time and biodistribution of polybutadiene-polyethylene oxide (PBd-PEO) polymersomes. For thi

Drug delivery systems for ovarian cancer treatment: a systematic review and meta-analysis of animal studies

Contains fulltext : 152141.pdf (publisher's version ) (Open Access)Current ovarian cancer treatment involves chemotherapy that has serious limitations, such as rapid clearance, unfavorable biodistribution and severe side effects. To overcome these limitations, drug delivery systems (DDS) have been developed to encapsulate chemotherapeutics for delivery to tumor cells. However, no systematic assessment of the efficacy of chemotherapy by DDS compared to free chemotherapy (not in a DDS) has been performed for animal studies. Here, we assess the efficacy of chemotherapy in DDS on survival and tumor growth inhibition in animal studies. We searched PubMed and EMBASE (via OvidSP) to systematically identify studies evaluating chemotherapeutics encapsulated in DDS for ovarian cancer treatment in animal studies. Studies were assessed for quality and risk of bias. Study characteristics were collected and outcome data (survival/hazard ratio or tumor growth inhibition) were extracted and used for meta-analyses. Meta-analysis was performed to identify and explore which characteristics of DDS influenced treatment efficacy. A total of 44 studies were included after thorough literature screening (2,735 studies found after initial search). The risk of bias was difficult to assess, mainly because of incomplete reporting. A total of 17 studies (377 animals) and 16 studies (259 animals) could be included in the meta-analysis for survival and tumor growth inhibition, respectively. In the majority of the included studies chemotherapeutics entrapped in a DDS significantly improved efficacy over free chemotherapeutics regarding both survival and tumor growth inhibition. Subgroup analyses, however, revealed that cisplatin entrapped in a DDS did not result in additional tumor growth inhibition compared to free cisplatin, although it did result in improved survival. Micelles did not show a significant tumor growth inhibition compared to free chemotherapeutics, which indicates that micelles may not be a suitable DDS for ovarian cancer treatment. Other subgroup analyses, such as targeted versus non-targeted DDS or IV versus IP administration route, did not identify specific characteristics of DDS that affected treatment efficacy. This systematic review shows the potential, but also the limitations of chemotherapy by drug delivery systems for ovarian cancer treatment. For future animal research, we emphasize that data need to be reported with ample attention to detailed reporting

Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Immunotherapy with checkpoint inhibitors demonstrates impressive improvements in the treatment of several types of cancer. Unfortunately, not all patients respond to therapy while severe immune-related adverse effects are prevalent. Currently, patient stratification is based on immunotherapy marker expression through immunohistochemical analysis on biopsied material. However, expression can be heterogeneous within and between tumor lesions, amplifying the sampling limitations of biopsies. Analysis of immunotherapy target expression by non-invasive quantitative molecular imaging with PET or SPECT may overcome this issue. In this review, an overview of tracers that have been developed for preclinical and clinical imaging of key immunotherapy targets, such as programmed cell death-1, programmed cell death ligand-1, IDO1 and cytotoxic T lymphocyte-associated antigen-4 is presented. We discuss important aspects to consider when developing such tracers and outline the future perspectives of molecular imaging of immunotherapy markers. Current techniques in immune checkpoint imaging and its potential for future applications

The in vivo fate of (225)Ac daughter nuclides using polymersomes as a model carrier

Contains fulltext : 209085.pdf (publisher's version ) (Open Access)Increasing attention is given to personalized tumour therapy, where alpha-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an alpha particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These 'free' daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of (225)Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing (225)Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free (213)Bi was assessed in different organs upon the injection [(225)Ac]Ac-polymersomes. The therapeutic effect of (225)Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing (225)Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy

The in vivo fate of 225Ac daughter nuclides using polymersomes as a model carrier

Increasing attention is given to personalized tumour therapy, where alpha-emitters can potentially play an important role. Alpha particles are ideal for localized cell killing because of their high linear energy transfer and short ranges. However, upon the emission of an alpha particle the daughter nuclide experiences a recoil energy large enough to ensure decoupling from any chemical bond. These ‘free’ daughter nuclides are no longer targeted to the tumour and can accumulate in normal tissue. In this paper, we used polymersomes as model carrier to evaluate the retention of recoiling daughters of 225Ac in vivo, and assessed their suitability as therapeutic agents. Vesicles containing 225Ac were injected intravenously in healthy mice, and intratumourally in tumour-bearing mice, and the relocation of free 213Bi was assessed in different organs upon the injection [225Ac]Ac-polymersomes. The therapeutic effect of 225Ac-containing vesicles was studied upon intratumoural injection, where treatment groups experienced no tumour-related deaths over a 115 day period. While polymersomes containing 225Ac could be suitable agents for long-term irradiation of tumours without causing significant renal toxicity, there is still a significant re-distribution of daughter nuclides throughout the body, signifying the importance of careful evaluation of the effect of daughter nuclides in targeted alpha therapy.JRC.G.I.5-Advanced Nuclear Knowledg

Therapeutic Efficacy of 225Ac-containing Polymersomes

Cancer, still presenting one of the major challenges in modern healthcare, leads to more than 8.8 million deaths annually. While the main treatment options include surgery, chemotherapy, and radiotherapy, increasing attention is given to brachytherapy in e.g. the treatment of prostate cancer. Advantages of brachytherapy, as compared to radical prostatectomy and external beam radiation therapy, lie in the much higher radiation doses which can be given to the tumour tissue whilst spearing healthy tissue. Whereas in classic brachytherapy careful placement of the seeds is still essential for optimal irradiation of the tumour, recently a movement towards the use of micro and nano particles for intratumoural administration has begun. These particles are able to distribute themselves to and within the tumour tissue, and can be labelled with either beta or alpha emitters. We have shown in the past that polymersomes are ideal candidates to be used in alpha therapy, as they are able to retain the recoiling daughter nuclides of 225Ac to a large extent, thus limiting the renal toxicity caused by recoiling daughters.JRC.G.I.5-Advanced Nuclear Knowledg

Direct comparison of the in vitro and in vivo stability of DFO, DFO* and DFOcyclo* for Zr-89-immunoPET

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Lyophilisomes as a new generation of drug delivery capsules

Item does not contain fulltextNanoparticulate drug delivery systems are currently explored to overcome critical challenges associated with classical administration forms. In this study, we present a drug delivery system based on a novel class of proteinaceous biodegradable nano/micro capsules, lyophilisomes. Lyophilisomes can be prepared from biomolecules without the need for amphiphilicity. Albumin-based lyophilisomes were prepared by freezing, annealing and lyophilizing, resulting in capsules ranging from 100 to 3000nm. Lyophilisomes were loaded with the anti-tumor drugs doxorubicin and curcumin using different concentrations and time/temperature regimes. Incubation in 0.1mg/ml doxorubicin or 1.0mg/ml curcumin resulted in an entrapment efficiency of 95+/-1% and 4+/-1%, respectively. This corresponds to a drug loading of 0.24mg doxorubicin per milligram albumin and 0.10mg curcumin per milligram albumin. Drug release profiles from doxorubicin and curcumin-loaded lyophilisomes were studied in culture medium and showed slow release for doxorubicin (2.7% after 72h), and rapid release for curcumin (55% after 72h). When applied to cells, non-loaded lyophilisomes did not influence cell viability, even at high concentrations (1mg/ml). Lyophilisomes were internalized by cells. When loaded with doxorubicin and curcumin, lyophilisomes strongly reduced cell proliferation and viability of SKOV-3 and HeLa cells, respectively, to a level similar or better compared to an equal amount of free drugs. In conclusion, albumin lyophilisomes show potential as (nano)carriers of drugs for tumor cell elimination