Smoking is linked to reproductive health issues for men and women. It also interferes with female David Rumpik, Ph. Monday—Sunday: 10am—11pm 1 person 2 hours 8 EUR. Clinical trials focusing on encapsulating and delivering chemotherapeutics in nanoparticles are abundant Table 2. Again, most of these systems are liposomes, with many of these liposomal systems having similar design features with already approved liposomal systems e. Still, few of these clinically investigated liposomal systems are introducing novel design features in the clinic.
However, particles ensure that the tumor receives this exact drug ratio for synergistic treatment. Other systems investigate polymeric or micelle formulations of already established chemotherapeutics and treatments. For example, there are a number of different paclitaxel or docetaxel micelles currently in clinical trials.
A broad approach, which aims to take advantage of a nanoparticle's control over circulation and biodistribution, is to target delivery of highly toxic anticancer drugs which would otherwise be too toxic in their free drug form. A number of other nanoparticle cancer therapies are designed to treat cancer in nonstandard methods.
This is done via the CpG motifs contained in the DNA in combination with adjuvant effects from the liposome. A number of other novel delivery nanoparticle systems are in clinical trials for cancer therapeutics such as targeted and stimuli responsive nanoparticles systems. Other liposomal nanoparticle formulations CAL02 are designed to be a broad antitoxin therapy, currently in a clinical trial for bacterial pneumonia, by competing with host cells for toxin binding.
Enceladus is developing liposomal formulated prednisolone Nanocort for broad treatment of acute inflammation. RadProtect utilizes micelle nanoparticles to confer radiation protection via release of the cytoprotective drug amifostine, and is being developed by Original BioMedicals. Interestingly, while nanoparticles and targeting antibodies are both approved for clinical use, systems combining these two technologies are lacking in both approved products and in clinical trials Table 3. Still, few technologies are being investigated in the clinic using chemically targeted means to enhance delivery of a number of therapeutics.
Examples of successful nanoparticle targeting in humans. Data show increased presence of p53 in patient's tumors as compared to negative control skin biopsy in same patients following the targeted therapy.
Reprinted with permission from AAAS. However, inorganic nanoparticles made from materials such as gold or iron oxide can be used for other stimuli responsive functions, such as thermal heating or magnetic control. Given that no active drug is used, and AuroLase is externally activated at the target site, this specific therapy has the potential for significantly reduced side effects. These efforts build on extensive preclinical testing, 98 , 99 , with early clinical results pointing to excellent tolerability in humans.
Hafnium oxide nanoparticles NBTXR3 , developed by Nanobiotix, utilize an external radiation source to enhance cell death at the radiation site via release of electrons. In preclinical animal models, NBTXR3 showed antitumor effects with similar to standard radiation therapies and early clinical results suggest a good safety profile in humans as well as encouraging antitumor results. In these studies, increased local temperature is achieved via microwave hypothermia, ultrasound, or radiofrequency thermal ablation.
Two other clinically investigated particles, LiPlaCis and RadProtect, respond to local biological cues to release their therapeutic. In the case of LiPlaCis, the liposomes degrade more rapidly in presence of phospholipase A2, which is more abundant in tumor tissues ; thus, the cisplatin payload is released only in the tumor and only in the target cells. RadProtect is a micelle linked by ferrous iron which chelates with transferrin for release of amifostine in the bloodstream. While amifostine release is not linked to uptake in a target cell, this method can be used to control the rate of amifostine release into the blood.
Each individual nanoparticle formulation will face unique challenges in their clinical translation yet the majority of nanomedicines will encounter many of the same challenges. These challenges are biological, technological, and study design related. Here, we will focus on key challenges the majority of intravenous nanoparticle formulations face and how these challenges present unique issues from a clinical and translational point of view.
Biological challenges including modulating biodistribution or controlling passage of nanoparticles across biological barriers and into target cells limit the effectiveness of all nanoparticle formulations.
Hideous Kinky is the story of two sisters seven and five years old traveling with their hippie mother from London to Morocco. Another strategy used in the clinical e. Antibody targeting tested in nonapproved particles, and as highlighted above, additionally confers advantages to internalization and crossing of biological barriers, especially in the case of transferrin targeted nanoparticles. Indeed, lack of increased efficacy is unacceptable and in most of these cases this direction should be taken, however, these studies should be designed such that they generate of knowledge in regards to fundamental nanoparticle interactions. ACS Nano. This test checks your body levels for all major heavy metals and toxins, and reveals where detox might be helpful. Kim Eastman.
As many preclinical studies and academic groups predominately focus on these challenges, we will not review them in detail, as it has been done previously. Additional focus will be placed on how both differences in animal and human diseases, and human disease heterogeneity, influence preclinical and clinical nanomedicine efforts. One of the main challenges facing the clinical translation of nanomedicines is controlling their biological fate e. Another strategy used in the clinical e. If successful, these systems will represent the first clinically approved examples of antibody targeted nanoparticles, which will likely facilitate the clinical investigation of additional targeted systems.
The main two strategies for approved nanomedicines in the clinic include using particles of specific sizes to increase accumulation of particles in tumor sites via the EPR effect or using liposomal systems that exhibit significantly enhanced binding and uptake into target cells. Antibody targeting tested in nonapproved particles, and as highlighted above, additionally confers advantages to internalization and crossing of biological barriers, especially in the case of transferrin targeted nanoparticles.
Interestingly, recent preclinical work has highlighted advantages of PEGylated particles beyond extended circulation, notably their diffusion in tissues and their abilities to pass through tight biological barriers. Still, efforts to further enhance barrier breaching and tissue penetration of nanoparticles should be considered, as it is widely accepted that nanoparticle payloads are more efficacious when distributed through pathological tissues, as opposed to just the periphery. A major issue with the clinical translation of nanoparticles is the division between preclinical studies in animals and clinical studies in humans.
An example of this is the EPR effect, which has certainly been established in small animal models, however, similar evidence is lacking for humans. Currently, approved particles do not directly address these issues; however, taking a close look at similarities between approved, and nonapproved clinically investigated, formulations it is clear that methods that have been shown to work broadly e. The issues of human disease heterogeneity and the general discrepancies between animals and humans become connected and further amplified by the limitations in analyzing their biological performance e.
For example, methods to analyze, and thereby quantitatively determine, the biological fate of nanoparticles in humans is exceedingly difficult given that the most quantitative techniques require organ isolation or tissue harvesting. However, certain technologies are better designed to handle these issues e. Overall, the majority of nanoparticles cannot be detected or analyzed in such a way; unfortunately, this will not only limit their analysis and interpretation of results, but it can also limit the translation of many would be successful therapies as it may not be possible to describe, and subsequently improve, clinical failures.
Biological challenges that intravenous nanoparticle formulations face. Here, we will focus on how the limits of current nanoparticle synthesis, experimental, and prediction technologies impact and influence their clinical success and integration. Clinical translation and integration relies on a consistent and reproducible product. Given the complexities in human disease, it is essential to have a consistent and highly reproducible formulation prior to the clinical trial stage. Synthesis issues have recently been encountered in the clinic, as a shortage of Doxil led to expedited approval and use of what was reported to be a generic but equivalent Doxil formulation, LipoDox.
As expected, the nanoparticle formulations offering the best performance in animal models, and thus the most potential, are the likely candidates for human translation and clinical trials. Unfortunately, the preclinical studies to determine the lead clinical candidates are for the most part not systematically designed optimized; often, formulations that are used in clinical trials are one of a handful of those investigated.
Technological challenges that intravenous nanoparticle formulations face. Methods to predict nanoparticle performance e. Combining these techniques with experimental results and devices designed to mimic physiological tissues and conditions e. Early efforts to correlate animal data to human clinical data have shown agreement in some aspects e. In contrast to the previously discussed issues are challenges relating to approval and study design in humans.
Specifically, study size and the timing of nanoparticle therapies in a treatment regimen impact how results from clinical studies are perceived. As such, clinical results greatly influence future nanoparticle clinical studies; special attention must be given to ensure that clinical trials are designed to extract the most information regarding nanoparticle interactions, fate, and function while still testing key hypotheses.
Perhaps surprisingly, many approved medications do not provide benefits to all who take them and this issue stems from original clinical study design that often overlooks trends in outliers which can affect a specific subset of patients. Nanomedicines provide a direct method to fine tune physicochemical properties on an individual basis that can tip the balance regarding a patient responding or not responding; however, to leverage these inherent advantages of nanoparticles, correlations between patients who either respond well or poorly and their previous medical history must be made.
Typically, the only instances where this is the case is for established and approved nanoparticle systems e. Given that most of these therapies are not established, and in many cases their tolerability is not known, it is safest and most appropriate to investigate their efficacy as a last resort.
As such, it is often the case that clinical trials are only available to patients who have stopped responding to treatments, as is the case with many cancer patients. While this represents a grand clinical challenge i. Empirical results are often the standard for preclinical studies. Indeed, it is similarly often the case that empirical results determine the commercial and clinical fate of nanoparticles in clinical trials; meaning, a binary result of improved survival or efficacy is enough to halt further investigations for a particular formulation.
Indeed, lack of increased efficacy is unacceptable and in most of these cases this direction should be taken, however, these studies should be designed such that they generate of knowledge in regards to fundamental nanoparticle interactions.
Many nanoparticle systems have been approved by either the FDA or EMA and are used in the clinic to either treat or diagnose disease. Significant efforts are pushing these same technologies further, by seeking approval for additional indications to impact clinical care even more. Beyond these efforts, there are a large number of clinical trials investigating novel nanoparticle systems that are, in some ways, more advanced that what has already been approved. Both of these functions are not available from any of the currently approved nanoparticle systems.
This progress in the clinic over the past 20 years since Doxil's approval has been made possible by the extensive efforts in preclinical, commercial, and clinical studies. Furthermore, the overall outlook of nanoparticle drug delivery systems is promising, as they are also being developed for treating and curing not only cancer, but a large number of other diseases.
National Center for Biotechnology Information , U. Journal List Bioeng Transl Med v. Bioeng Transl Med. Published online Jun 3. Aaron C.
Anselmo 1 and Samir Mitragotri 2. Anselmo 1 David H. Samir Mitragotri 2 Dept. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Email: ude. Received Jan 23; Accepted Feb This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC. Keywords: clinic, translational medicine, clinical translation, clinical trials, drug delivery, nanomedicine, nanoparticles.
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Open in a separate window. Figure 1. Table 1 Clinically approved intravenous nanoparticle therapies and diagnostics, grouped by their broad indication. Cancer nanoparticle medicines Many clinically approved nanoparticle formulations are used in treating various cancers at a variety of stages. Nanoparticles for vaccines, anesthetics, fungal treatments, and macular degeneration Nanoparticles, or in these cases liposomes, are also used in a number of other clinical applications Table 1.
Table 2 Intravenous nanoparticle therapies and diagnostics which have not been clinically approved and are currently undergoing clinical trials not yet recruiting, recruiting, or active , grouped by particle type as well as well as application. Previously approved nanoparticles By seeking approval for additional indications, currently approved nanoparticle systems experience a more direct path to clinical approval as compared to a newer, developing, technology. Cancer nanoparticle medicine As cancer nanomedicines were approved by the FDA over 20 years ago, it is not surprising that these currently approved nanoparticles are investigated in the largest number of current clinical trials.
Cancer nanomedicines Cancer nanomedicines receive the most attention of all nanoparticle indications or applications in clinical trials for therapeutic purposes e. Gene therapy Efforts to package and deliver siRNA or mRNA in nanoparticles for therapeutic applications, especially in cancer, are beginning to enter the clinic Table 2. Chemotherapeutics and anticancer drugs Clinical trials focusing on encapsulating and delivering chemotherapeutics in nanoparticles are abundant Table 2.
Targeted delivery systems Interestingly, while nanoparticles and targeting antibodies are both approved for clinical use, systems combining these two technologies are lacking in both approved products and in clinical trials Table 3.
Figure 2. Biological challenges Biological challenges including modulating biodistribution or controlling passage of nanoparticles across biological barriers and into target cells limit the effectiveness of all nanoparticle formulations. Biodistribution modulation One of the main challenges facing the clinical translation of nanomedicines is controlling their biological fate e. Heterogeneity of human disease and relevant animal models A major issue with the clinical translation of nanoparticles is the division between preclinical studies in animals and clinical studies in humans.
The interplay between biological challenges The issues of human disease heterogeneity and the general discrepancies between animals and humans become connected and further amplified by the limitations in analyzing their biological performance e. Figure 3. Figure 4. Predicting nanoparticle efficacy and performance Methods to predict nanoparticle performance e.
Studies extracting fundamental information Empirical results are often the standard for preclinical studies. Anselmo AC, Mitragotri S. An overview of clinical and commercial impact of drug delivery systems. J Control Release. Torchilin VP. Nat Rev Drug Discov. Svenson S. Clinical translation of nanomedicines. Clinical translation of nanomedicine. Chem Rev. The emerging nanomedicine landscape.
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