The Experts below are selected from a list of 52623 Experts worldwide ranked by ideXlab platform
Twan Lammers - One of the best experts on this subject based on the ideXlab platform.
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Challenges in Nanomedicine clinical translation
Drug Delivery and Translational Research, 2020Co-Authors: Josbert M. Metselaar, Twan LammersAbstract:New Nanomedicine formulations and novel applications of nanomedicinal drugs are reported on an almost daily basis. While academic progress and societal promise continue to shoot for the stars, industrial acceptance and clinical translation are being looked at increasingly critically. We here discuss five key challenges that need to be considered when aiming to promote the clinical translation of Nanomedicines. We take the perspective of the end-stage users and consequently address the developmental path in a top-down manner. We start off by addressing central and more general issues related to practical and clinical feasibility, followed by more specific preclinical, clinical, and pharmaceutical aspects that nanomedicinal product development entails. We believe that being more aware of the end user’s perspective already early on in the Nanomedicine development path will help to better oversee the efforts and investments needed, and to take optimally informed decisions with regard to market opportunities, target disease indication, clinical trial design, therapeutic endpoints, preclinical models, and formulation specifications. Critical reflections on and careful route planning in Nanomedicine translation will help to promote the success of nanomedicinal drugs. Graphical abstract
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Smart cancer Nanomedicine
Nature nanotechnology, 2019Co-Authors: Roy Van Der Meel, Fabian Kiessling, Einar Sulheim, Yang Shi, Willem J. M. Mulder, Twan LammersAbstract:Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve Nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer Nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer Nanomedicine therapies.
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Combining Nanomedicine and Immunotherapy
Accounts of chemical research, 2019Co-Authors: Yang Shi, Twan LammersAbstract:Nanomedicine holds significant potential to improve the efficacy of cancer immunotherapy. Thus far, Nanomedicines, i.e., 1-100(0) nm sized drug delivery systems, have been primarily used to improve the balance between the efficacy and toxicity of conjugated or entrapped chemotherapeutic drugs. The clinical performance of cancer Nanomedicines has been somewhat disappointing, which is arguably mostly due to the lack of tools and technologies for patient stratification. Conversely, the clinical progress made with immunotherapy has been spectacular, achieving complete cures and inducing long-term survival in advanced-stage patients. Unfortunately, however, immunotherapy only works well in relatively small subsets of patients. Increasing amounts of preclinical and clinical data demonstrate that combining Nanomedicine with immunotherapy can boost therapeutic outcomes, by turning "cold" nonimmunoresponsive tumors and metastases into "hot" immunoresponsive lesions. Nano-immunotherapy can be realized via three different approaches, in which Nanomedicines are used (1) to target cancer cells, (2) to target the tumor immune microenvironment, and (3) to target the peripheral immune system. When targeting cancer cells, Nanomedicines typically aim to induce immunogenic cell death, thereby triggering the release of tumor antigens and danger-associated molecular patterns, such as calreticulin translocation, high mobility group box 1 protein and adenosine triphosphate. The latter serve as adjuvants to alert antigen-presenting cells to take up, process and present the former, thereby promoting the generation of CD8+ cytotoxic T cells. Nanomedicines targeting the tumor immune microenvironment potentiate cancer immunotherapy by inhibiting immunosuppressive cells, such as M2-like tumor-associated macrophages, as well as by reducing the expression of immunosuppressive molecules, such as transforming growth factor beta. In addition, Nanomedicines can be employed to promote the activity of antigen-presenting cells and cytotoxic T cells in the tumor immune microenvironment. Nanomedicines targeting the peripheral immune system aim to enhance antigen presentation and cytotoxic T cell production in secondary lymphoid organs, such as lymph nodes and spleen, as well as to engineer and strengthen peripheral effector immune cell populations, thereby promoting anticancer immunity. While the majority of immunomodulatory Nanomedicines are in preclinical development, exciting results have already been reported in initial clinical trials. To ensure efficient translation of nano-immunotherapy constructs and concepts, we have to consider biomarkers in their clinical development, to make sure that the right Nanomedicine formulation is combined with the right immunotherapy in the right patient. In this context, we have to learn from currently ongoing efforts in nano-biomarker identification as well as from partially already established immuno-biomarker initiatives, such as the Immunoscore and the cancer immunogram. Together, these protocols will help to capture the nano-immuno status in individual patients, enabling the identification and use of individualized and improved Nanomedicine-based treatments to boost the performance of cancer immunotherapy.
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Imaging Nanomedicine-Based Drug Delivery: a Review of Clinical Studies
Molecular Imaging and Biology, 2018Co-Authors: Twan Lammers, Rafael T. M. De RosalesAbstract:Imaging plays a key role in the preclinical evaluation of Nanomedicine-based drug delivery systems and it has provided important insights into their mechanism of action and therapeutic effect. Its role in supporting the clinical development of Nanomedicine products, however, has been less explored. In this review, we summarize clinical studies in which imaging has provided valuable information on the pharmacokinetics, biodistribution, and target site accumulation of Nanomedicine-based drug delivery systems. Importantly, these studies provide convincing evidence on the uptake of Nanomedicines in tumors, confirming that the enhanced permeability and retention (EPR) effect is a real phenomenon in patients, albeit with fairly high levels of inter- and intraindividual variability. It is gradually becoming clear that imaging is critically important to help address this high heterogeneity. In support of this notion, a decent correlation between Nanomedicine uptake in tumors and antitumor efficacy has recently been obtained in two independent studies in patients, exemplifying that image-guided drug delivery can help to pave the way towards individualized and improved Nanomedicine therapies.
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Enhancing Tumor Penetration of Nanomedicines
Biomacromolecules, 2017Co-Authors: Qingxue Sun, Twan Lammers, Fabian Kiessling, Tarun Ojha, Yang ShiAbstract:Tumor-targeted Nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical Nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially due to the inefficient tumor penetration caused by the tumor microenvironment (high density of cells and extracellular matrix, increased interstitial fluid pressure). Furthermore, tumor penetration of Nanomedicines is significantly influenced by physicochemical characteristics, such as size, surface chemistry, and shape. The effect of size on tumor penetration has been exploited to design Nanomedicines with switchable size to tackle this challenge. Moreover, several pharmacological and physical approaches have been developed to enhance the tumor penetration of Nanomedicines, by penetration-promoting ligands, intratumoral drug release, and modulating the tumor microenvironment and vasculature. Overall, these effor...
Fabian Kiessling - One of the best experts on this subject based on the ideXlab platform.
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Smart cancer Nanomedicine
Nature nanotechnology, 2019Co-Authors: Roy Van Der Meel, Fabian Kiessling, Einar Sulheim, Yang Shi, Willem J. M. Mulder, Twan LammersAbstract:Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve Nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer Nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer Nanomedicine therapies.
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Enhancing Tumor Penetration of Nanomedicines
Biomacromolecules, 2017Co-Authors: Qingxue Sun, Twan Lammers, Fabian Kiessling, Tarun Ojha, Yang ShiAbstract:Tumor-targeted Nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical Nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially due to the inefficient tumor penetration caused by the tumor microenvironment (high density of cells and extracellular matrix, increased interstitial fluid pressure). Furthermore, tumor penetration of Nanomedicines is significantly influenced by physicochemical characteristics, such as size, surface chemistry, and shape. The effect of size on tumor penetration has been exploited to design Nanomedicines with switchable size to tackle this challenge. Moreover, several pharmacological and physical approaches have been developed to enhance the tumor penetration of Nanomedicines, by penetration-promoting ligands, intratumoral drug release, and modulating the tumor microenvironment and vasculature. Overall, these effor...
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Theranostic Nanomedicine.
Accounts of chemical research, 2011Co-Authors: Twan Lammers, Wim E Hennink, Gert Storm, Silvio Aime, Fabian KiesslingAbstract:Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically administered (chemo)therapeutic agents. Many different types of Nanomedicines have been evaluated over the years, including for instance liposomes, polymers, micelles and antibodies, and a significant amount of evidence has been obtained showing that these submicrometer-sized carrier materials are able to improve the balance between the efficacy and the toxicity of therapeutic interventions. Besides for therapeutic purposes, Nanomedicine formulations have in recent years also been increasingly employed for imaging applications. Moreover, paralleled by advances in chemistry, biology, pharmacy, nanotechnology, medicine and imaging, several different systems have been developed in the last decade in which disease diagnosis and therapy are combined. These so-called (nano) theranostics contain both a drug and an imaging agent within a single formulation, and they can be used for various different purposes. In this Account, we summarize several exemplary efforts in this regard, and we show that theranostic Nanomedicines are highly suitable systems for monitoring drug delivery, drug release and drug efficacy. The (pre)clinically most relevant applications of theranostic Nanomedicines relate to their use for validating and optimizing the properties of drug delivery systems, and to their ability to be used for pre-screening patients and enabling personalized medicine. Regarding the former, the combination of diagnostic and therapeutic agents within a single formulation provides real-time feedback on the pharmacokinetics, the target site localization and the (off-target) healthy organ accumulation of Nanomedicines. Various examples of this will be highlighted in this Account, illustrating that by non-invasively visualizing how well carrier materials are able to deliver pharmacologically active agents to the pathological site, and how well they are able to prevent them from accumulating in potentially endangered healthy tissues, important information can be obtained for optimizing the basic properties of drug delivery systems, as well as for improving the balance between the efficacy and the toxicity of targeted therapeutic interventions. Regarding personalized medicine, it can be reasoned that only in patients which show high levels of target site accumulation, and which respond well to the first couple of treatment cycles, targeted therapy should be continued, and that in those in which this is not the case, other therapeutic options should be considered. Based on these insights, we expect that ever more efforts will be invested in developing theranostic Nanomedicines, and that these systems and strategies will contribute substantially to realizing the potential of personalized medicine.
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Nanotheranostics and image-guided drug delivery: current concepts and future directions.
Molecular pharmaceutics, 2010Co-Authors: Twan Lammers, Wim E Hennink, Fabian Kiessling, Gert StormAbstract:Nanomedicine formulations aim to improve the biodistribution and the target site accumulation of systemically applied (chemo-) therapeutics. Various different passively and actively targeted Nanomedicines have been evaluated over the years, based e.g. on liposomes, polymers, micelles and antibodies, and a significant amount of (pre-) clinical evidence has been obtained showing that these 5−200 nm sized carrier materials are able to improve the therapeutic index of low-molecular-weight drugs. Besides for therapeutic purposes, however, Nanomedicine formulations have also been more and more used for imaging applications, as well as, in recent years, for theranostic approaches, i.e. for systems and strategies in which disease diagnosis and therapy are combined. Potential applications of theranostic Nanomedicine formulations range from the noninvasive assessment of the biodistribution and the target site accumulation of low-molecular-weight drugs, and the visualization of drug distribution and drug release at ...
Yang Shi - One of the best experts on this subject based on the ideXlab platform.
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Smart cancer Nanomedicine
Nature nanotechnology, 2019Co-Authors: Roy Van Der Meel, Fabian Kiessling, Einar Sulheim, Yang Shi, Willem J. M. Mulder, Twan LammersAbstract:Nanomedicines are extensively employed in cancer therapy. We here propose four strategic directions to improve Nanomedicine translation and exploitation. (1) Patient stratification has become common practice in oncology drug development. Accordingly, probes and protocols for patient stratification are urgently needed in cancer Nanomedicine, to identify individuals suitable for inclusion in clinical trials. (2) Rational drug selection is crucial for clinical and commercial success. Opportunistic choices based on drug availability should be replaced by investments in modular (pro)drug and nanocarrier design. (3) Combination therapies are the mainstay of clinical cancer care. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. (4) Immunotherapy is revolutionizing the treatment of cancer. Nanomedicines can modulate the behaviour of myeloid and lymphoid cells, thereby empowering anticancer immunity and immunotherapy efficacy. Alone and especially together, these four directions will fuel and foster the development of successful cancer Nanomedicine therapies.
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Combining Nanomedicine and Immunotherapy
Accounts of chemical research, 2019Co-Authors: Yang Shi, Twan LammersAbstract:Nanomedicine holds significant potential to improve the efficacy of cancer immunotherapy. Thus far, Nanomedicines, i.e., 1-100(0) nm sized drug delivery systems, have been primarily used to improve the balance between the efficacy and toxicity of conjugated or entrapped chemotherapeutic drugs. The clinical performance of cancer Nanomedicines has been somewhat disappointing, which is arguably mostly due to the lack of tools and technologies for patient stratification. Conversely, the clinical progress made with immunotherapy has been spectacular, achieving complete cures and inducing long-term survival in advanced-stage patients. Unfortunately, however, immunotherapy only works well in relatively small subsets of patients. Increasing amounts of preclinical and clinical data demonstrate that combining Nanomedicine with immunotherapy can boost therapeutic outcomes, by turning "cold" nonimmunoresponsive tumors and metastases into "hot" immunoresponsive lesions. Nano-immunotherapy can be realized via three different approaches, in which Nanomedicines are used (1) to target cancer cells, (2) to target the tumor immune microenvironment, and (3) to target the peripheral immune system. When targeting cancer cells, Nanomedicines typically aim to induce immunogenic cell death, thereby triggering the release of tumor antigens and danger-associated molecular patterns, such as calreticulin translocation, high mobility group box 1 protein and adenosine triphosphate. The latter serve as adjuvants to alert antigen-presenting cells to take up, process and present the former, thereby promoting the generation of CD8+ cytotoxic T cells. Nanomedicines targeting the tumor immune microenvironment potentiate cancer immunotherapy by inhibiting immunosuppressive cells, such as M2-like tumor-associated macrophages, as well as by reducing the expression of immunosuppressive molecules, such as transforming growth factor beta. In addition, Nanomedicines can be employed to promote the activity of antigen-presenting cells and cytotoxic T cells in the tumor immune microenvironment. Nanomedicines targeting the peripheral immune system aim to enhance antigen presentation and cytotoxic T cell production in secondary lymphoid organs, such as lymph nodes and spleen, as well as to engineer and strengthen peripheral effector immune cell populations, thereby promoting anticancer immunity. While the majority of immunomodulatory Nanomedicines are in preclinical development, exciting results have already been reported in initial clinical trials. To ensure efficient translation of nano-immunotherapy constructs and concepts, we have to consider biomarkers in their clinical development, to make sure that the right Nanomedicine formulation is combined with the right immunotherapy in the right patient. In this context, we have to learn from currently ongoing efforts in nano-biomarker identification as well as from partially already established immuno-biomarker initiatives, such as the Immunoscore and the cancer immunogram. Together, these protocols will help to capture the nano-immuno status in individual patients, enabling the identification and use of individualized and improved Nanomedicine-based treatments to boost the performance of cancer immunotherapy.
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Enhancing Tumor Penetration of Nanomedicines
Biomacromolecules, 2017Co-Authors: Qingxue Sun, Twan Lammers, Fabian Kiessling, Tarun Ojha, Yang ShiAbstract:Tumor-targeted Nanomedicines have been extensively applied to alter the drawbacks and enhance the efficacy of chemotherapeutics. Despite the large number of preclinical Nanomedicine studies showing initial success, their therapeutic benefit in the clinic has been rather modest, which is partially due to the inefficient tumor penetration caused by the tumor microenvironment (high density of cells and extracellular matrix, increased interstitial fluid pressure). Furthermore, tumor penetration of Nanomedicines is significantly influenced by physicochemical characteristics, such as size, surface chemistry, and shape. The effect of size on tumor penetration has been exploited to design Nanomedicines with switchable size to tackle this challenge. Moreover, several pharmacological and physical approaches have been developed to enhance the tumor penetration of Nanomedicines, by penetration-promoting ligands, intratumoral drug release, and modulating the tumor microenvironment and vasculature. Overall, these effor...
David Tai Leong - One of the best experts on this subject based on the ideXlab platform.
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Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness
Nature Nanotechnology, 2019Co-Authors: Fei Peng, Magdiel Inggrid Setyawati, Jie Kai Tee, Xianguang Ding, Jinping Wang, Min En Nga, David Tai LeongAbstract:Nanoparticles used in Nanomedicine can induce increased vascular leakiness and therefore accelerate intravasation and extravasation of cancer cells, exacerbating existing metastasis and promoting the appearance of new metastatic sites. While most cancer Nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin–VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future Nanomedicines, especially Nanomedicine to treat cancer.
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Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness.
Nature nanotechnology, 2019Co-Authors: Fei Peng, Magdiel Inggrid Setyawati, Jie Kai Tee, Xianguang Ding, Jinping Wang, Min En Nga, David Tai LeongAbstract:While most cancer Nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin-VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future Nanomedicines, especially Nanomedicine to treat cancer.
Scott E. Mcneil - One of the best experts on this subject based on the ideXlab platform.
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Evaluating Nanomedicines: Obstacles and Advancements.
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Magdalena Swierczewska, Rachael M. Crist, Scott E. McneilAbstract:Continued advancements in nanotechnology are expanding the boundaries of medical research, most notably as drug delivery agents for treatment against cancer. Drug delivery with nanotechnology can offer greater control over the biodistribution of therapeutic agents to improve the therapeutic index. In the last 20 years, a number of Nanomedicines have transitioned into the clinic. As Nanomedicines evolve, techniques to properly evaluate their safety and efficacy must also evolve. Characterization methods for nano-based materials must be adapted to the demands of Nanomedicine developers and regulators. This second edition book provides updated characterization protocols designed to address the clinical potential of Nanomedicines during their preclinical development. In this chapter, the characterization challenges of nanoparticles intended for drug delivery will be discussed, along with examples of advancements and improvements in Nanomedicine characterization.
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nanomaterial standards for efficacy and toxicity assessment
Wiley Interdisciplinary Reviews-nanomedicine and Nanobiotechnology, 2010Co-Authors: Pavan P Adiseshaiah, Jennifer B Hall, Scott E. McneilAbstract:Decreased toxicity via selective delivery of cancer therapeutics to tumors has become a hallmark achievement of nanotechnology. In order to be optimally efficacious, a systemically administered Nanomedicine must reach cancer cells in sufficient quantities to elicit a response and assume its active form within the tumor microenvironment (e.g., be taken up by cancer cells and release a toxic component once within the cytosol or nuclei). Most Nanomedicines achieve selective tumor accumulation via the enhanced permeability and retention (EPR) effect or a combination of the EPR effect and active targeting to cellular receptors. Here, we review how the fundamental physicochemical properties of a Nanomedicine (its size, charge, hydrophobicity, etc.) can dramatically affect its distribution to cancerous tissue, transport across vascular walls, and retention in tumors. We also discuss how nanoparticle characteristics such as stability in the blood and tumor, cleavability of covalently bound components, cancer cell uptake, and cytotoxicity contribute to efficacy once the nanoparticle has reached the tumor's interstitial space. We elaborate on how tumor vascularization and receptor expression vary depending on cancer type, stage of disease, site of implantation, and host species, and review studies which have demonstrated that these variations affect tumor response to Nanomedicines. Finally, we show how knowledge of these properties (both of the nanoparticle and the cancer/tumor under study) can be used to design meaningful in vivo tests to evaluate nanoparticle efficacy. WIREs Nanomed Nanobiotechnol 2010 2 99–112 For further resources related to this article, please visit the WIREs website.
