Mononuclear but not polymorphonuclear phagocyte depletion increases circulation times and improves mammary tumor-homing efficiency of donor bone marrow-derived monocytes

Tumor associated macrophages are an essential part of the tumor microenvironment. Consequently, bone marrow-derived monocytes (BMDMs) are continuously recruited to tumors and are therefore seen as ideal delivery vehicles with tumor-targeting properties. By using immune cell depleting agents and macroscopic in vivo fluorescence imaging, we demonstrated that removal of endogenous monocytes and macrophages (but not neutrophils) leads to an increased tumor accumulation of exogenously administered BMDMs. By means of intravital microscopy (IVM), we confirmed our macroscopic findings on a cellular level and visualized in real time the migration of the donor BMDMs in the tumors of living animals. Moreover, IVM also revealed that clodronate-mediated depletion drastically increases the circulation time of the exogenously administered BMDMs. In summary, these new insights illustrate that impairment of the mononuclear phagocyte system increases the circulation time and tumor accumulation of donor BMDMs

Profiling target engagement and cellular uptake of cRGD-decorated clinical-stage core-crosslinked polymeric micelles

Polymeric micelles are increasingly explored for tumor-targeted drug delivery. CriPec® technology enables the generation of core-crosslinked polymeric micelles (CCPMs) based on thermosensitive (mPEG-b-pHPMAmLacn) block copolymers, with high drug loading capacity, tailorable size, and controlled drug release kinetics. In this study, we decorated clinical-stage CCPM with the αvβ3 integrin-targeted cyclic arginine-glycine-aspartic acid (cRGD) peptide, which is one of the most well-known active targeting ligands evaluated preclinically and clinically. Using a panel of cell lines with different expression levels of the αvβ3 integrin receptor and exploring both static and dynamic incubation conditions, we studied the benefit of decorating CCPM with different densities of cRGD. We show that incubation time and temperature, as well as the expression levels of αvβ3 integrin by target cells, positively influence cRGD-CCPM uptake, as demonstated by immunofluorescence staining and fluorescence microscopy. We demonstrate that even very low decoration densities (i.e., 1 mol % cRGD) result in increased engagement and uptake by target cells as compared to peptide-free control CCPM, and that high cRGD decoration densities do not result in a proportional increase in internalization. In this context, it should be kept in mind that a more extensive presence of targeting ligands on the surface of nanomedicines may affect their pharmacokinetic and biodistribution profile. Thus, we suggest a relatively low cRGD decoration density as most suitable for in vivo application

The battle of “nano” paclitaxel

Paclitaxel (PTX) is one of the three most widely used chemotherapeutic agents, together with doxorubicin and cisplatin, and is first or second line treatment for several types of cancers. In 2000, Taxol, the conventional formulation of PTX, became the best-selling cancer drug of all time with annual sales of 1.6 billion. In 2005, the introduction of the albumin-based formulation of PTX, known as Abraxane, ended Taxol's monopoly of the PTX market. Abraxane's ability to push the Taxol innovator and generic formulations aside attracted fierce competition amongst competitors worldwide to develop their own unique, new and improved formulation of PTX. At this time there are at least 18 companies focused on pre-clinical and/or clinical development of nano-formulations of PTX. These pharmaceutical companies are investing substantial capital to capture a share of the lucrative global PTX market. It is hoped that any formulation that dominates the market will result in tangible benefits to patients in terms of both survival and quality of life. Given all of this activity, here we address the question: Who is going to win the battle of “nano” paclitaxel

The battle of "nano" paclitaxel

Paclitaxel (PTX) is one of the three most widely used chemotherapeutic agents, together with doxorubicin and cisplatin, and is first or second line treatment for several types of cancers. In 2000, Taxol, the conventional formulation of PTX, became the best-selling cancer drug of all time with annual sales of 1.6 billion. In 2005, the introduction of the albumin-based formulation of PTX, known as Abraxane, ended Taxol's monopoly of the PTX market. Abraxane's ability to push the Taxol innovator and generic formulations aside attracted fierce competition amongst competitors worldwide to develop their own unique, new and improved formulation of PTX. At this time there are at least 18 companies focused on pre-clinical and/or clinical development of nano-formulations of PTX. These pharmaceutical companies are investing substantial capital to capture a share of the lucrative global PTX market. It is hoped that any formulation that dominates the market will result in tangible benefits to patients in terms of both survival and quality of life. Given all of this activity, here we address the question: Who is going to win the battle of "nano" paclitaxel

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders

A paradigm shift in cancer nanomedicine: from traditional tumor targeting to leveraging the immune system

Twenty-five years after the approval of the first anticancer nanodrug, we have to start re(de)fining tumor-targeted drug delivery alongside advances in immuno-oncology. Given that cancer is characterized by an immunological imbalance that goes beyond the primary tumor, we should focus on targeting, engaging, and modulating cancer-associated immune cells in the tumor microenvironment (TME), circulation, and immune cell-enriched tissues. When designed and applied rationally, nanomedicines will assist in restoring the immunological equilibrium at the whole-body level, which holds potential not only for cancer therapy, but also for the treatment of a range of other disorders

Intravital microscopy for real-time monitoring of drug delivery and nanobiological processes

Intravital microscopy (IVM) expands our understanding of cellular and molecular processes, with applications ranging from fundamental biology to (patho)physiology and immunology, as well as from drug delivery to drug processing and drug efficacy testing. In this review, we highlight modalities, methods and model organisms that make up today's IVM landscape, and we present how IVM - via its high spatiotemporal resolution - enables analysis of metabolites, small molecules, nanoparticles, immune cells, and the (tumor) tissue microenvironment. We furthermore present examples of how IVM facilitates the elucidation of nanomedicine kinetics and targeting mechanisms, as well as of biological processes such as immune cell death, host-pathogen interactions, metabolic states, and disease progression. We conclude by discussing the prospects of IVM clinical translation and examining the integration of machine learning in future IVM practice