File Name: medical nanotechnology and nanomedicine .zip
The use of nanotechnology in medicine offers some exciting possibilities. Some techniques are only imagined, while others are at various stages of testing, or actually being used today. Nanotechnology in medicine involves applications of nanoparticles currently under development, as well as longer range research that involves the use of manufactured nano-robots to make repairs at the cellular level sometimes referred to as nanomedicine. Whatever you call it, the use of nanotechnology in the field of medicine could revolutionize the way we detect and treat damage to the human body and disease in the future, and many techniques only imagined a few years ago are making remarkable progress towards becoming realities.
Opportunistic choices based on drug availability should be replaced by investments in modular pro drug and nanocarrier design. Nanomedicines synergize with pharmacological and physical co-treatments, and should be increasingly integrated in multimodal combination therapy regimens. 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. Nanomedicine holds potential to improve anticancer therapy 1. Traditionally, nanomedicines are used to modulate the biodistribution and the target site accumulation of systemically administered chemotherapeutic drugs, thereby improving the balance between their efficacy and toxicity.
In preclinical settings, nanomedicines typically increase tumour growth inhibition and prolong survival as compared to non-formulated drugs, but in clinical practice, patients often only benefit from nanomedicines because of reduced or altered side effects 2. Despite the recent approval of several nanomedicinal anticancer drugs, such as Onivyde liposomal irinotecan and Vyxeos liposomal daunorubicin plus cytarabine , the success rate of clinical translation remains relatively low.
In this context, the striking imbalance between the ever-increasing number of preclinical studies reporting the development of ever more complex nanomedicines on the one hand, and the relatively small number of nanomedicine products approved for clinical use on the other hand, has become the focus of intense debate 3 , 4.
Multiple biological, pharmaceutical and translational barriers contribute to this imbalance 5. Pharmaceutical barriers encompass both nanoformulation- and production-associated aspects. These range from a proper stability in the bloodstream, a beneficial biodistribution, an acceptable toxicity profile, and rational mechanisms for drug release, biodegradation and elimination, to issues related to intellectual property position, cost of goods, cost of manufacturing, upscaling and batch-to-batch reproducibility.
In terms of clinical translation, the key challenge is to select the right drug and the right combination regimen, and to apply them in the right disease indication and the right patient population.
To make sure that we start tackling the right translational challenges, we must define key strategic directions, to guide nanomedicine clinical trial design and ensure clear therapeutic benefits to patients. We propose four directions to boost nanomedicine performance and exploitation, that is, smart patient stratification, smart drug selection, smart combination therapies and smart immunomodulation Fig. Four directions are proposed that — on their own and especially together — will promote the translation and exploitation of nanomedicinal anticancer drugs.
Modern oncology drug development extensively employs biomarkers and companion diagnostics for patient stratification. Companion diagnostics help to address the high heterogeneity that is typical of cancer, and they have been instrumental in the successful clinical translation of molecularly targeted drugs, such as growth factor receptor-blocking antibodies and tyrosine kinase inhibitors.
This more broadly applicable biomarker is termed microsatellite instability-high MSI-H or mismatch repair deficient dMMR , and it is used for patient stratification in case of treatment with immune checkpoint inhibiting antibodies 9. Remarkably, neither biomarkers nor companion diagnostics are currently used to tailor nanomedicine treatments in patients Fig. Notable exceptions in this regard are antibody—drug conjugates, which are often excluded from nanomedicine lists because they are more biotechnological than nanotechnological but should be included according to the generally accepted definition.
Four antibody—drug conjugates have recently received regulatory approval: Kadcyla ado-trastuzumab emtansine, anti-HER2 ; Adcetris brentuximab vedotin, anti-CD30 ; Besponsa inotuzumab ozogamicin, anti-CD22 and Mylotarg gemtuzumab ozogamicin, anti-CD In all of these cases, the intrinsic availability of biomarkers for patient stratification has played a key role in their successful clinical development.
Several probes and protocols can be employed for patient stratification, including circulating tumour cell CTC analysis, immunohistochemical IHC assessment of the tumour microenvironment, and direct and indirect imaging of nanomedicine tumour accumulation. These approaches vary in simplicity, specificity and applicability for passively versus actively targeted nanomedicines.
Liquid biomarkers are the most straightforward and least invasive, but may not be predictive enough to serve as standalone biomarkers for tailoring nanomedicine treatment. Tissue biomarkers are easily available, but are likely more useful for actively than passively targeted nanomedicines, and their predictive power needs to be explored. Imaging biomarkers can rely on approved contrast agents and companion nanodiagnostics, which are available off the shelf.
This contributes to simplicity, but the information obtained may not be specific enough. Nanotheranostics provide highly specific information on the target site accumulation of the formulation in question, but are more challenging from a translational point of view. In the case of more traditional cancer nanomedicines, which are based on liposomes, polymeric nanoparticles and micelles, the lack of integrating biomarkers may explain recent failures in the clinic.
Notable examples include BIND docetaxel-loaded prostate-specific membrane antigen PSMA -targeted polyethylene glycol-polylactic acid nanoparticles 10 , CRLX campthotecin-loaded polyethylene glycol-cyclodextrin nanoparticles 11 and NK paclitaxel-loaded polyethylene glycol-polyaspartate-based micelles 12 , which all failed to produce convincing response rates in unstratified patient cohorts. Retrospectively, one can ask whether it was realistic to believe that these nanodrugs could achieve significant response rates in mixed and heavily pre-treated patients not stratified in any way.
To improve the clinical impact of cancer nanomedicines, we should therefore start to establish biomarkers for patient stratification, and we should also integrate nanomedicines — ideally already from early clinical development stages onwards — in combination regimens.
Nanomedicine accumulation in solid tumours is generally based on the enhanced permeability and retention EPR effect. This concept, however, has come under increasing criticism in recent years. Some nanomedicine investigators even claim that the EPR effect exists only in mice, not in humans. To address this, strategies and materials are needed to monitor and predict nanomedicine accumulation and efficacy In the case of ligand-targeted nanomedicines, such as BIND, which relies on both EPR and active recognition of receptors overexpressed at pathological sites, patient stratification can in principle be achieved relatively easily, for example, via immunohistochemically assessing PSMA expression in tumour biopsies This strategy warrants further investigation, as PSMA-positive and other CTC can potentially be employed both as a biomarker for patient stratification and as an indicator of therapeutic responses.
In this context, it is important to keep the basic principles of active tumour targeting in mind. Active targeting relies to a significant extent on passive targeting, which requires prolonged circulation times. Introducing targeting ligands often promotes nanomedicine clearance from the blood stream, via opsonization and accelerated uptake by the mononuclear phagocytic system MPS Before they can bind to target cells, actively targeted nanomedicines furthermore have to extravasate out of the blood vessels in tumours and metastases, penetrate deep into the interstitium and cross multiple cell layers.
The latter can suffer from the so called binding-site barrier 18 , which may hinder nanomedicine penetration Nanocarrier size plays a crucial role in determining the added value of active targeting.
Active targeting did, however, change the intratumoural compartmentalization of the nanocarriers, increasing their uptake by cancer cells.
In line with this, it was shown that 70—80 nm-sized HER2-targeted gold nanoparticles 21 and nm-sized HER2-targeted liposomes 22 accumulate to a higher extent in cancer cells than in macrophages, but do not achieve higher tumour concentrations. These scenarios underline the importance of critically reflecting on the added value of active targeting in cancer nanomedicine applications.
The use of liquid and tissue biopsy biomarkers is less straightforward in the case of passively targeted nanomedicines, as there are no surface receptors available for immunohistochemical staining or CTC assessment. Accordingly, these nanomedicines likely require imaging probes and protocols for patient stratification Fig. Several recent studies have established companion nanodiagnostics and nanotheranostics to address EPR effect heterogeneity and to predict nanotherapy outcomes 23 , Ferumoxytol-enhanced MRI correlated with therapeutic nanoparticle uptake in tumour-associated macrophages TAM and enabled prediction of tumour accumulation and anti-tumour efficacy In the clinic, ferumoxytol-enhanced MRI in patients with mixed solid tumours demonstrated that higher ferumoxytol accumulation levels correlated with greater lesion size reductions following treatment with liposomal irinotecan Onivyde Although such MRI-based companion diagnostics are relatively cost effective, they require pre- and post-contrast MRI, which complicates the analysis, particularly in regions with variable soft tissue contrast.
An alternative companion nanodiagnostic approach is positron emission tomography PET imaging with 89 Zr-labelled nanoreporter liposomes, which accurately predicted Doxil accumulation and efficacy using a single PET scan Besides predicting tumour accumulation, imaging biomarkers can also be employed to assess responses to nanomedicine therapies. Tumour metabolism — as opposed to that in healthy cells — largely relies on aerobic glycolysis, a phenomenon known as the Warburg effect A related and highly interesting future direction in this regard is imaging and targeting of amino acid metabolism in tumours.
Nanomedicine formulations interfering with these pathways and imaging agents capturing these pathways are envisaged to hold significant potential for improving cancer therapy.
Cancer nanomedicines can in principle be co-loaded with drugs and with imaging agents, to directly visualize and quantify target site accumulation.
Such theranostic formulations provide the most specific information on biodistribution and tumour accumulation, thereby ruling out issues related to differences in physicochemical and pharmacokinetic properties between nanodiagnostics and nanotherapeutics. However, these formulations are more difficult to translate to the clinic and lack the flexibility and versatility of companion nanodiagnostics, which allow for example, for decision making prior to starting treatment.
A pioneering clinical study involving nanotheranostics recently showed that PET combined with computed tomography CT can assess the tumour accumulation of 64 Cu-labelled HER2-targeted liposomal doxorubicin in HER2-positive metastatic breast cancer patients.
Higher target site accumulation levels corresponded with more favourable therapeutic outcomes Interestingly, molecules such as doxorubicin and alendronate can function as chelators, to enable easy and efficient in vivo monitoring of target site accumulation This smart and straightforward approach to obtain radiolabelled liposomal drugs opens up new theranostic opportunities for patient stratification in cancer nanomedicine.
It has to be kept in mind, however, that nanomedicine accumulation in tumours must be followed by payload release to achieve therapeutic benefits, since for most nanomedicines, the formulated drugs have to be liberated to become pharmacologically active. Drugs can be spontaneously released from nanocarriers in tumours, for example free doxorubicin is released from Doxil 37 , and this can also be mediated by TAM Monitoring drug release in vivo is possible using contrast-enhanced MRI and optical imaging.
Both methods, however, have limited translational relevance, because of the potential toxicity associated with co-loading high amounts of gadolinium in nanomedicines, and because of the limited penetration depth of optical imaging, respectively.
Consequently, studies in two-dimensional 2D cell culture, in 3D spheroids and in preclinical mouse models should encompass mechanistic analyses on drug release and target cell uptake upon nanomedicine-mediated delivery. Furthermore, future analyses should set out to evaluate if histopathological assessment of tumour biopsies can help to stratify responders from non-responders.
Tumour biopsies are readily available for the vast majority of patients, and scoring, for example, vessel and macrophage density and distribution is hypothesized to be reasonably useful for predicting nanomedicine accumulation and efficacy.
Rational drug selection is crucial for making cancer nanomedicines clinically and commercially successful. Preclinically, most nanomedicine publications deal with re-formulating established chemotherapeutic drugs, and all clinically approved cancer nanomedicines antibody—drug conjugates excluded are based on standard cytostatics, such as doxorubicin, daunorubicin, paclitaxel, vincristine and irinotecan For all of these agents, nanomedicine re-formulation improves the therapeutic index, but typically mostly by attenuating side effects, not by inducing significantly improved therapeutic responses.
In addition, future efforts in cancer nanomedicine drug development should focus more on the use of nanocarrier materials for the delivery of non-standard drugs such as biologics, and they should increasingly encompass smart strategies such as drug derivatization, modular nanocarrier design and library screening Fig. Rational drug selection is crucial to ensure clinical and commercial success.
Multiple strategies can be envisaged to connect the right drug to the right nanocarrier for the right indication. Drug classes: Nanomedicines can be loaded with different types of anticancer drugs, including standard chemotherapeutics, highly potent toxins, biologics and nucleic acids.
Prodrugs can be engineered to ensure optimal compatibility with nanocarrier formulations, including, for example, drug coupling via ester linkers to an aliphatic chain for efficient incorporation in lipid-based nanomedicines. Screening: Nanomedicine libraries can be produced via high-throughput technologies. Various labelling and analytical techniques can be employed to identify nanomedicine candidates with optimal properties for in vivo performance.
Standard chemotherapeutic drugs, such as doxorubicin and paclitaxel, do come with side effects, but are overall reasonably well tolerated by patients; otherwise they would not have become drug products.
Newer, more potent, agents, such as auristatins, are too toxic to be administered to patients in free form. Antibody—drug conjugates, however, typically have very low payloads.
To explore formulations with higher auristatin payloads, polymeric nanoparticles containing thousands of drug molecules were developed. These nanoparticles achieved efficient tumour growth inhibition and prolonged survival as compared to standard of care cisplatin in a patient-derived xenograft model of ovarian cancer, without significant systemic toxicity Similarly, a potent Aurora B kinase inhibitor — which in free form caused unacceptable side effects in a phase II clinical trial — increased efficacy and reduced toxicity in multiple preclinical models upon reformulation in PEG-PLA-based nanoparticles Nucleic acid agents critically rely on protection against degradation in systemic circulation and they generally require intracellular delivery.
The nanotechnology used in Onpattro patisiran, liver-targeted siRNA-containing lipid nanoparticles for the treatment of transthyretin-related hereditary amyloidosis 46 is facilitating the development of other genetic nanomedicines, such as RNA-based vaccines for treating infections and cancer 47 ,
In the last decades, nanotechnology-based tools started to draw the attention of research worldwide. They offer economic, rapid, effective, and highly specific solutions for most medical issues. As a result, the international demand of nanomaterials is expanding very rapidly. In medicine, various applications of nanotechnology proved their potential to revolutionize medical diagnosis, immunization, treatment, and even health care products. The loading substances can be coupled with a large set of nanoparticles NPs by many means: chemically conjugation , physically encapsulation , or via adsorption. The use of the suitable loading nanosubstance depends on the application purpose.
Metrics details. Nanomedicine and nano delivery systems are a relatively new but rapidly developing science where materials in the nanoscale range are employed to serve as means of diagnostic tools or to deliver therapeutic agents to specific targeted sites in a controlled manner. Nanotechnology offers multiple benefits in treating chronic human diseases by site-specific, and target-oriented delivery of precise medicines. Recently, there are a number of outstanding applications of the nanomedicine chemotherapeutic agents, biological agents, immunotherapeutic agents etc. The current review, presents an updated summary of recent advances in the field of nanomedicines and nano based drug delivery systems through comprehensive scrutiny of the discovery and application of nanomaterials in improving both the efficacy of novel and old drugs e.
Request PDF | Medical Nanotechnology and Nanomedicine | Review "Given that nanomedicine involves the application of fields as diverse as.
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Various applications of nanoscale science to the field of medicine have resulted in the ongoing development of the subfield of nanomedicine. Within the past several years, there has been a concurrent proliferation of academic journals, textbooks, and other professional literature addressing fundamental basic science research and seminal clinical developments in nanomedicine.
Challenges in Nanomaterials Characterization View all 4 Articles. Several scientific areas have benefited significantly from the introduction of nanotechnology and the respective evolution. This is especially noteworthy in the development of new drug substances and products. This review focuses on the introduction of nanomedicines in the pharmaceutical market, and all the controversy associated to basic concepts related to these nanosystems, and the numerous methodologies applied for enhanced knowledge. Due to the properties conferred by the nanoscale, the challenges for nanotechnology implementation, specifically in the pharmaceutical development of new drug products and respective regulatory issues are critically discussed, mainly focused on the European Union context. Finally, issues pertaining to the current applications and future developments are presented.
Science always strives to find an improved way of doing things and nanoscience is one such approach. Nanomaterials are suitable for pharmaceutical applications mostly because of their size which facilitates absorption, distribution, metabolism and excretion of the nanoparticles. Whether labile or insoluble nanoparticles, their cytotoxic effect on malignant cells has moved the use of nanomedicine into focus. Since nanomedicine can be described as the science and technology of diagnosing, treating and preventing diseases towards ultimately improving human health, a lot of nanotechnology options have received approval by various regulatory agencies. Nanodrugs also have been discovered to be more precise in targeting the desired site, hence maximizing the therapeutic effects, while minimizing side-effects on the rest of the body.
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Comptes Rendus de l'Académie des Sciences. Nanomedicine, Nanotechnology in medicine. Nanomédecine et nanotechnologies pour la.