Two‐dimensional (2D) nanomaterials are currently explored as novel photothermal agents because of their ultrathin structure, high specific surface area, and unique optoelectronic properties. In ...addition to single photothermal therapy (PTT), 2D nanomaterials have demonstrated significant potential in PTT‐based synergistic therapies. In this Minireview, we summarize the recent progress in 2D nanomaterials for enhanced photothermal cancer therapy over the last five years. Their unique optical properties, typical synthesis methods, and surface modification are also covered. Emphasis is placed on their PTT and PTT‐synergized chemotherapy, photodynamic therapy, and immunotherapy. The major challenges of 2D photothermal agents are addressed and the promising prospects are also presented.
Cancer therapy: Recent progress in 2D nanomaterials for photothermal therapy including their optical properties, synthesis methods, surface modification, and applications is reviewed. The unique properties and advantages of 2D nanomaterials have been successfully used in photothermal therapy and combined photothermal therapy. This application will continue to be attractive and needs further exploration.
Nanoparticle‐based therapeutic, prevention, and detection modalities have the potential to greatly impact how diseases are diagnosed and managed in the clinic. With the wide range of nanomaterials ...available, the rational design of nanocarriers on an application‐specific basis has become increasingly commonplace. Here, a comprehensive overview is provided on an emerging platform: cell‐membrane‐coating nanotechnology. As a fundamental unit of biology, cells carry out a wide range of functions, including the remarkable ability to interface and interact with their surrounding environment. Instead of attempting to replicate such functions via synthetic techniques, researchers are now directly leveraging naturally derived cell membranes as a means of bestowing nanoparticles with enhanced biointerfacing capabilities. This top‐down technique is facile, highly generalizable, and has the potential to greatly augment existing nanocarriers. Further, the introduction of a natural membrane substrate onto nanoparticles surfaces has enabled additional applications beyond those traditionally associated with nanomedicine. Despite its relative youth, there exists an impressive body of literature on cell membrane coating, which is covered here in detail. Overall, there is still significant room for development, as researchers continue to refine existing workflows while finding new and exciting applications that can take advantage of this developing technology.
Cell membrane coating represents an emerging nanotechnology. By cloaking nanomaterials in a layer of natural cell membrane, which can be derived from a variety of cell types, it is possible to fabricate nanoplatforms with enhanced surface functionality. This can lead to increased nanoparticle performance in complex biological environments, which can benefit applications like drug delivery, imaging, phototherapies, immunotherapies, and detoxification.
Cancer immunotherapies that train or stimulate the inherent immunological systems to recognize, attack, and eradicate tumor cells with minimal damage to healthy cells have demonstrated promising ...clinical responses in recent years. However, most of these immunotherapeutic strategies only benefit a small subset of patients and cause systemic autoimmune side effects in some patients. Immunogenic cell death (ICD)‐inducing modalities not only directly kill cancer cells but also induce antitumor immune responses against a broad spectrum of solid tumors. Such strategies for generating vaccine‐like functions could be used to stimulate a “cold” tumor microenvironment to become an immunogenic, “hot” tumor microenvironment, working in synergy with immunotherapies to increase patient response rates and lead to successful treatment outcomes. This Minireview will focus on nanoparticle‐based treatment modalities that can induce and enhance ICD to potentiate cancer immunotherapy.
Nanoparticle‐mediated immunogenic cell death directly kills cancer cells and induces antitumor immune responses. Such in situ vaccination strategies can be used to activate the tumor microenvironment to synergize with cancer immunotherapies to improve patient response rates and treatment outcomes.
Liposome as a revolutionizing carrier, has exhibited favorable aspects in drug delivery. However, there are numerous challenges affecting its effectiveness. Hypersensitivity, accelerated blood ...clearance, opsonization, uptake by reticulo-endothelial system, and also immune suppression are known as the dominant manifestations of immune-related effects. They may cause failure to achieve the proof of regulatory approvals. In this review, liposome challenges in biologic environment have been discussed. Moreover, opsonization and liposome interactions with innate and acquired immune system have been investigated. Immune system elements including the corresponding receptors and cells were reviewed in this regard. By exploring immune related interactions of the liposome, it could be possible for the formulators to be aware of the immune related interactions of the administered liposomal formulation. On the other hand, immune targeted liposomes for immunotherapy and vaccination purposes could also be developed.
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•Opsonizing proteins change protein corona and affect the fate of liposomes.•Accelerated blood clearance of the liposomes is time and frequency dependent.•Composition, charge and modifications of liposomes change the immune interactions.•Liposome clearance, and CAPRA induction should be studied in pre-formulation step.•Immune-targeted liposomes in favor or against immune system are being developed.
Regulatory T (T
) cells, although vital for immune homeostasis, also represent a major barrier to anti-cancer immunity, as the tumour microenvironment (TME) promotes the recruitment, differentiation ...and activity of these cells
. Tumour cells show deregulated metabolism, leading to a metabolite-depleted, hypoxic and acidic TME
, which places infiltrating effector T cells in competition with the tumour for metabolites and impairs their function
. At the same time, T
cells maintain a strong suppression of effector T cells within the TME
. As previous studies suggested that T
cells possess a distinct metabolic profile from effector T cells
, we hypothesized that the altered metabolic landscape of the TME and increased activity of intratumoral T
cells are linked. Here we show that T
cells display broad heterogeneity in their metabolism of glucose within normal and transformed tissues, and can engage an alternative metabolic pathway to maintain suppressive function and proliferation. Glucose uptake correlates with poorer suppressive function and long-term instability, and high-glucose conditions impair the function and stability of T
cells in vitro. T
cells instead upregulate pathways involved in the metabolism of the glycolytic by-product lactic acid. T
cells withstand high-lactate conditions, and treatment with lactate prevents the destabilizing effects of high-glucose conditions, generating intermediates necessary for proliferation. Deletion of MCT1-a lactate transporter-in T
cells reveals that lactate uptake is dispensable for the function of peripheral T
cells but required intratumorally, resulting in slowed tumour growth and an increased response to immunotherapy. Thus, T
cells are metabolically flexible: they can use 'alternative' metabolites in the TME to maintain their suppressive identity. Further, our results suggest that tumours avoid destruction by not only depriving effector T cells of nutrients, but also metabolically supporting regulatory populations.
Exosomes hold great potential in therapeutic development. However, native exosomes usually induce insufficient effects in vivo and simply act as drug delivery vehicles. Herein, we synthesize ...responsive exosome nano‐bioconjugates for cancer therapy. Azide‐modified exosomes derived from M1 macrophages are conjugated with dibenzocyclooctyne‐modified antibodies of CD47 and SIRPα (aCD47 and aSIRPα) through pH‐sensitive linkers. After systemic administration, the nano‐bioconjugates can actively target tumors through the specific recognition between aCD47 and CD47 on the tumor cell surface. In the acidic tumor microenvironment, the benzoic‐imine bonds of the nano‐bioconjugates are cleaved to release aSIRPα and aCD47 that can, respectively, block SIRPα on macrophages and CD47, leading to abolished “don't eat me” signaling and improved phagocytosis of macrophages. Meanwhile, the native M1 exosomes effectively reprogram the macrophages from pro‐tumoral M2 to anti‐tumoral M1.
Ok, take a bite: Responsive exosome nano‐bioconjugates were constructed by engineering M1 exosomes with aCD47 and aSIRPα linked with a pH‐sensitive bond. After systemic administration, the synergism of specific targeting by aCD47, blocking of “don't eat me” signaling by aCD47 and aSIRPα, and M2 reprogramming by M1 exosomes resulted in a potent anticancer effect.
In this study, an organic semiconducting pro‐nanostimulant (OSPS) with a near‐infrared (NIR) photoactivatable immunotherapeutic action for synergetic cancer therapy is presented. OSPS comprises a ...semiconducting polymer nanoparticle (SPN) core and an immunostimulant conjugated through a singlet oxygen (1O2) cleavable linkers. Upon NIR laser irradiation, OSPS generates both heat and 1O2 to exert combinational phototherapy not only to ablate tumors but also to produce tumor‐associated antigens. More importantly, NIR irradiation triggers the cleavage of 1O2‐cleavable linkers, triggering the remote release of the immunostimulants from OSPS to modulate the immunosuppressive tumor microenvironment. Thus, the released tumor‐associated antigens in conjunction with activated immunostimulants induce a synergistic antitumor immune response after OSPS‐mediated phototherapy, resulting in the inhibited growth of both primary/distant tumors and lung metastasis in a mouse xenograft model, which is not observed for sole phototherapy.
An organic semiconducting pro‐nanostimulant was developed for synergetic cancer therapy. Only upon near‐infrared (NIR) irradiation is the pro‐nanostimulant activated to simultaneously exert phototherapy and checkpoint blockade immunotherapy, inhibiting the growth of primary/distant tumors and significantly suppressing the lung metastasis without causing any obvious in vivo toxicity.
Mit der Einführung der Therapieallergene-Verordnung (TAV) sollen die im Bestandsmarkt befindlichen, bisher nicht zugelassenen Therapieallergene hinsichtlich ihres Nutzen-Risiko Verhältnisses ...überprüft werden als Grundvoraussetzung für eine arzneimittelrechtliche Zulassung. Die pharmazeutischen Unternehmer sind aufgefordert klinische Studienprogramme durchzuführen. An diesem Prozess wird Kritik geübt, da dieser zu langen Übergangsfristen führen kann, sodass Patienten über wahrscheinlich zwei Jahrzehnte hinweg mit Präparaten behandelt werden, deren Wirksamkeit bisher nicht belegt ist und ggf. niemals belegt wird. So kann die TAV durch pharmazeutische Unternehmer genutzt werden, um finanzielle Mittel aus der Patientenversorgung trotz fehlendem bzw. ausstehendem Wirksamkeitsnachweis abzuschöpfen.
Ziel dieser Arbeit ist es, die kritischen Präparate aufzulisten, für welche seit Beginn der TAV 2008 keine öffentlich zugängliche Studienaktivität zu verzeichnen ist. Hierfür wird das europäische Clinical Trials Register (clinicaltrialsregister.eu) und das amerikanische Studienregister (ClinicalTrials.gov) systematisch durchsucht. Hierbei soll folgende im Sinne der TAV folgerichtige Hypothese überprüft werden: „Für die im TAV-Prozess befindlichen Präparate wurden in den vergangenen Jahren Studienprogramme durchgeführt, die Präparate stehen mehrheitlich kurz vor einer Zulassung durch das PEI“.
Die Hypothese wird mit den Erkenntnissen dieser Arbeit widerlegt. Tatsächlich lässt sich aktuell kein Präparat identifizieren, welches kurz vor der Zulassung im Rahmen der TAV steht. 61 Präparate befinden sich derzeit noch im TAV-Prozess, lediglich zwei Präparate haben diesen bereits erfolgreich durchlaufen. Es gilt zu bedenken, dass mit einem Studienprogramm mehrere Präparate derselben Produktgruppe und derselben homologen Gruppe zugelassen werden können, indem die Zulassung zum Beispiel für Frühblüher (Birke, Erle, Hasel) und Birke vergeben wird. Werden die insgesamt 63 (61+2) Präparate in den homologen Gruppen – Bäume, Gräser, Milben und Mischungen – zusammengefasst, bleiben 33 Präparate, die sich wie folgt klassifizieren lassen:•17 Präparate ohne Studienbeginn (inkl. ein Präparat mit einer fehlgeschlagenen Studie ohne weitere Aktivität): Für 12 der 33 Präparate kann keine Studienaktivität festgestellt werden. Für ein weiteres Präparat wurde eine Negativstudie gefunden. Da es sich hierbei jedoch um eine ältere Phase III-Studie (Studienbeginn im Jahre 2008) ohne vorherige Phase II-Studie handelt, wäre diese wahrscheinlich ohnehin ohne Relevanz für den TAV-Prozess geblieben. Da für dieses Präparat ansonsten keine weitere Aktivität nach der fehlgeschlagenen Studie zu erkennen ist, wurde dieses in die Liste der Präparate ohne Studienaktivität einklassifiziert, somit 13 Präparate (12+1). Bei weiteren vier Präparaten handelt es ich um Mischungen (drei Gräser-Bäume- und eine Gräser-Kräuter-Mischung) ebenfalls ohne Studienbeginn im Rahmen der TAV. Daher wurde für insgesamt 17 Präparate keine zielführende Studienaktivität im Rahmen der TAV begonnen.•Ein Präparat mit Zulassung im Rahmen der TAV (zwei Studien): Ein Präparat hat den Prozess erfolgreich durchlaufen. Hierfür wurden zwei Studien durchgeführt.•15 Präparate im Zulassungsprozess (33 Studien): Zu den 15 restlichen Präparaten wurden insgesamt 33 Studienaktivitäten (Phase II- & Phase III-Studien) gesichtet.
Fazit: Insgesamt 33 Präparate mit insgesamt 36 Studien (inkl. o.g. Negativstudie) im TAV Prozess: Für die 33 im TAV Prozess befindlichen Präparate werden/wurden 36 Studien (Dosisfindungsstudien: Phase II oder Wirksamkeitsstudien: Phase III) im Rahmen des Screenings gefunden, die potentiell für die TAV Relevanz haben könnten. Für 15 dieser Studien wurden ordnungsgemäß die Ergebnisse im europäischen Studienregister hinterlegt. Für weitere 13 Studien sind die Ergebnisse im Studienregister nicht hinterlegt, obwohl diese als abgeschlossen gekennzeichnet sind. Für vier Studien wurden keine Informationen im europäischen Studienregister hinterlegt, der Status dieser Studien bleibt ungewiss. Vier Studien sind noch nicht abgeschlossen.
Eine Empfehlung zur Verordnung eines bestimmten SIT-Präparates durch einen verantwortungsvollen Arzt kann jedoch erst nach angemessenem Beleg für dessen Wirksamkeit ausgesprochen werden. Für Präparate, welche über zehn Jahre nach Einführung der TAV noch keinen Studienbeginn verzeichnen, ist es sehr fraglich, ob eine Zulassung noch erreicht werden kann bzw. diese überhaupt angestrebt wird. Zudem veröffentlichen manche pharmazeutischen Unternehmer offensichtlich ihre Studienergebnisse nicht. Andere Unternehmen sind Ihren Pflichten nachgekommen.
Dieser Publikation ist zusammenfassend zu entnehmen, dass es für die drei inhalativen Hauptallergene (Gräser, Bäume und Milben) bereits heute eine Auswahl an zugelassenen, evidenzbasierten und wirksamen Alternativen, sowohl für die subkutane (SCIT), als auch die sublinguale (SLIT) Applikation von verschiedenen Herstellen auf dem Markt gibt. Der Einsatz von zugelassenen und nachweislich wirksamen Therapien ist im Sinne einer leitliniengerechten, sinnvollen Versorgung der Patienten unerlässlich.
With the introduction of the Therapy Allergens Ordinance (TAV) the previously unapproved therapeutic allergens on the existing market need to be checked for their risk-benefit ratio as a basic prerequisite for approval under pharmaceutical law. This process is criticized because it can lead to long transition periods so that patients will probably be treated for two decades with preparations whose effectiveness has not yet been proven and may never be proven.
The aim of this work is to list the critical preparations for which no publicly accessible study activity has been recorded since the beginning of the TAV in 2008. For this purpose, the European Clinical Trials Register (clinicaltrialsregister.eu) and the American study register (ClinicalTrials.gov) are systematically searched. The following hypothesis, consistent with the TAV, will be checked: “In the past years, study programs were carried out for the preparations in the process of the TAV - the majority of these preparations are about to be approved by PEI”. The hypothesis is refuted with the findings of this work. In fact, no preparation can currently be identified that is about to be TAV approved. 61 preparations are currently in the TAV process; only two preparations have already passed this successfully. If the total of 63 (61+2) preparations are combined in the homologous groups – trees, grasses, mites and mixtures –, there are 33 preparations that can be classified as follows:•One preparation with approval as part of TAV (two studies)•17 preparations where no study has so far been initiated (including one preparation with a failed study without further activity)•15 preparations in the approval process (33 studies)
For the 33 preparations in the TAV process, 36 studies (phase II and III) that may potentially be relevant for TAV were found as part of the screening. For 15 of these studies the results have duly been entered in the European study register. The results of another 13 studies have not been stored in the study register although they are marked as completed. No information has been stored in the European study register for four studies so that the status of these studies remains unclear. Four studies have not yet been completed.
Responsible doctors can make recommendations for the prescription of a certain SIT preparation only if there is adequate evidence of its effectiveness. For preparations that have not yet started studies more than ten years after the introduction of the TAV, it is very doubtful whether approval can still be obtained or whether it is even being sought. For the three main inhaled allergens (grasses, trees and mites) there is already a selection of approved, evidence-based and effective alternatives for both subcutaneous (SCIT) and sublingual (SLIT) application from various manufacturers on the market. The use of therapies that have been approved and proven effective is essential in terms of guideline-compliant, sensible care for patients.
Despite the widespread applications of manganese oxide nanomaterials (MONs) in biomedicine, the intrinsic immunogenicity of MONs is still unclear. MnOx nanospikes (NSs) as tumor microenvironment ...(TME)‐responsive nanoadjuvants and immunogenic cell death (ICD) drugs are proposed for cancer nanovaccine‐based immunotherapy. MnOx NSs with large mesoporous structures show ultrahigh loading efficiencies for ovalbumin and tumor cell fragment. The combination of ICD via chemodynamic therapy and ferroptosis inductions, as well as antigen stimulations, presents a better synergistic immunopotentiation action. Furthermore, the obtained nanovaccines achieve TME‐responsive magnetic resonance/photoacoustic dual‐mode imaging contrasts, while effectively inhibiting primary/distal tumor growth and tumor metastasis.
MnOx nanospikes serve as tumor microenvironment‐responsive nanoadjuvants and immunogenic cell death drugs for cancer nanovaccine‐based immunotherapy. They induce immunogenic cell death via chemodynamic therapy and ferroptosis, thereby enhancing antitumor immunity and antimetastatic effect. Key: glutathione (GSH), glutathione peroxidase 4 (GPX4), magnetic resonance imaging (MRI), near infrared (NIR), photoacoustic imaging (PAI).
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