The Evolution of Tumor‐Targeted Drug Delivery: From the EPR Effect to Nanoswimmers

Zoabi, Nour; Golani-Armon, Adi; Zinger, Assaf; Reshef, Maayan; Yaari, Zvi; Vardi-Oknin, Dikla; Shatsberg, Zohar; Shomar, Aseel; Shainsky‐Roitman, Janna; Schroeder, Avi

doi:10.1002/ijch.201300061

Cited by 5 publications

(3 citation statements)

References 132 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, according to this model, oxygenation of hypoxic tissue due to PFC nanodroplets can only become comparable with enhanced oxygen breathing when the amount of PFC material is both evenly distributed in the tissue and is greater than 8% of the total tumor volume (Supplementary Figure S4). However, since no more than ~10% of total injected nanoscale agents typically accumulate inside solid tumors through the EPR effect 86, practically achieving such a high volume ratio in the tumor as predicted by the model is unlikely.…”

Section: Resultsmentioning

confidence: 99%

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing

Yun¹,

Bernards²,

Hoang³

et al. 2019

Nanotheranostics

View full text Add to dashboard Cite

Nanoscale perfluorocarbon (PFC) droplets have enormous potential as clinical theranostic agents. They are biocompatible and are currently used in vivo as contrast agents for a variety of medical imaging modalities, including ultrasound, computed tomography, photoacoustic and 19 F-magnetic resonance imaging. PFC nanodroplets can also carry molecular and nanoparticulate drugs and be activated in situ by ultrasound or light for targeted therapy. Recently, there has been renewed interest in using PFC nanodroplets for hypoxic tumor reoxygenation towards radiosensitization based on the high oxygen solubility of PFCs. Previous studies showed that tumor oxygenation using PFC agents only occurs in combination with enhanced oxygen breathing. However, recent studies suggest that PFC agents that accumulate in solid tumors can contribute to radiosensitization, presumably due to tumor reoxygenation without enhanced oxygen breathing. In this study, we quantify the impact of oxygenation due to PFC nanodroplet accumulation in tumors alone in comparison with other reoxygenation methodologies, in particular, carbogen breathing. Methods: Lipid-stabilized, PFC (i.e., perfluorooctyl bromide, CF 3 (CF 2 ) 7 Br, PFOB) nanoscale droplets were synthesized and evaluated in xenograft prostate (DU145) tumors in male mice. Biodistribution assessment of the nanodroplets was achieved using a fluorescent lipophilic indocarbocyanine dye label (i.e., DiI dye) on the lipid shell in combination with fluorescence imaging in mice (n≥3 per group). Hypoxia reduction in tumors was measured using PET imaging and a known hypoxia radiotracer, [ 18 F]FAZA (n≥ 3 per group). Results: Lipid-stabilized nanoscale PFOB emulsions (mean diameter of ~250 nm), accumulated in the xenograft prostate tumors in mice 24 hours post-injection. In vivo PET imaging with [ 18 F]FAZA showed that the accumulation of the PFOB nanodroplets in the tumor tissues alone significantly reduced tumor hypoxia, without enhanced oxygen (i.e., carbogen) breathing. This reoxygenation effect was found to be comparable with carbogen breathing alone. Conclusion: Accumulation of nanoscale PFOB agents in solid tumors alone successfully reoxygenated hypoxic tumors to levels comparable with carbogen breathing alone, an established tumor oxygenation method. This study confirms that PFC agents can be used to reoxygenate hypoxic tumors in addition to their current applications as multifunctional theranostic agents.

show abstract

Section: Resultsmentioning

confidence: 99%

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing

Yun¹,

Bernards²,

Hoang³

et al. 2019

Nanotheranostics

View full text Add to dashboard Cite

show abstract

“…While the vaginal drug delivery route has been known since ancient times (Hussain & Ahsan 2005), the idea of utilizing sperm-hybrid micro-bio-robot for fertilization as well as the possibility to use the synthetic attachment to carry anti-cancer drugs have been conceived (Magdanz & Schmidt 2014). Therapeutics may be attached to sperm cells together with synthetic attachments to guide their motion or incorporated into the sperm head to take advantage of the sperm's abilities to protect molecular cargo and deliver it from cell to cell (Zoabi et al 2013). Such a target cell might also be the oocyte; for example, to deliver genes or diagnostic tools with the sperm directly in the process of fertilization.…”

Section: Targeted Drug Therapymentioning

confidence: 99%

Sperm-hybrid micromotors: on-board assistance for nature’s bustling swimmers

2020

View full text Add to dashboard Cite

Sperm cells that cannot swim and orient properly compromise male fertility. Such defects are responsible for male infertility regardless of the actual quality of the most important content, the sperm’s DNA. Synthetic micromotors are engineered devices that are able to swim in (body) fluids and microscopic environments, similar to flagellated cells like sperm. Coupled together, a sperm-hybrid micromotor embodies the concept of bringing the sperm cell together with artificial components that assist or replace defective functions of the cell, helping it to pursue its goal without interfering with its health, enabling the process of assisted fertilization and further embryo development all inside the body. Non-invasive, remote-controlled in vivo applicability is the key quality of such hybrid microdevices. Assisted reproduction with the help of micromotors is in the focus of this review, although other biomedical applications that arise from the powerful combination of sperm cell and synthetic enhancement are also discussed and summarized. Details are provided about different fabrication processes and cell-material coupling strategies, and the way from proof-of-concept studies to in vivo experiments in animals is outlined.

show abstract

“…Passive targeting is solely dependent on Enhanced Permeability and Retention (EPR) effect [2,3] Active targeting on the other hand can be of two types; (i) homing to disease sites by loading targeting agents with ligands or antibodies that bind specifically to biomarkers uniquely expressed/secreted in diseased regions [4] or (ii) self-propelling drug carriers [5]. EPR is a direct effect of poor and leaky vasculature that is normally seen in disease sites (e.g., tumor microenvironments) and is only effective for upto 10% retention of therapeutics at these sites [6]. While antibody and ligand directed nanoparticles show high levels of specific uptake by diseased cells, their targeting rates were still found to be low, as their accumulation in target sites (< 10%) is still dependent on the EPR effect [7,8].…”

Section: Introductionmentioning

confidence: 99%

Factors Affecting Bacterial Propagation towards Tumor Microenvironments

Koduvayur¹

2016

MOJPB

View full text Add to dashboard Cite

This paper provides a detailed analysis to identify factors that improve bacterial targeting times to tumor microenvironments. We utilize the "active flagellar" motion characteristic of the bacterial movement to present a continuous time Markov model and a first passage time analysis to determine the factors that affect the mean time taken for injected bacteria to reach a tumor micro environment. We have determined 3 major factors that play a role in determining mean targeting times: (i) the population of the injected bacteria, (ii) the distance between the region of injection and the tumor microenvironment and (iii) the directional efficiency of the injected bacteria. Of these 3 factors our results show that the directional efficiency is the most significant factor that affects the time taken by different bacterial species to reach the tumor micro environment. While distance between the tumor micro environment and the region of injection also plays an important role, population of bacteria is most ineffective, especially for large directional efficiency. Our model matches well with some existing experimental results.

show abstract

The Evolution of Tumor‐Targeted Drug Delivery: From the EPR Effect to Nanoswimmers

Cited by 5 publications

References 132 publications

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing

Perfluorocarbon nanodroplets can reoxygenate hypoxic tumors in vivo without carbogen breathing

Sperm-hybrid micromotors: on-board assistance for nature’s bustling swimmers

Factors Affecting Bacterial Propagation towards Tumor Microenvironments

Contact Info

Product

Resources

About