Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

Background Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. Results Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. Conclusions This work provides a new paradigm for the treatment of residual HCC after IRFA. Graphical Abstract

EPR Effect-Based Tumor Targeted Nanomedicine: A Promising Approach for Controlling Cancer

Cancer remains the major threat to human health in most advanced countries in the world [...]

Application of Nanoparticles in the Treatment of Lung Cancer With Emphasis on Receptors

Lung cancer is one of the malignant tumors that has seen the most rapid growth in terms of morbidity and mortality in recent years, posing the biggest threat to people’s health and lives. In recent years, the nano-drug loading system has made significant progress in the detection, diagnosis, and treatment of lung cancer. Nanomaterials are used to specifically target tumor tissue to minimize therapeutic adverse effects and increase bioavailability. It is achieved primarily through two mechanisms: passive targeting, which entails the use of enhanced penetration and retention (EPR) effect, and active targeting, which entails the loading recognition ligands for tumor marker molecules onto nanomaterials. However, it has been demonstrated that the EPR effect is effective in rodents but not in humans. Taking this into consideration, researchers paid significant attention to the active targeting nano-drug loading system. Additionally, it has been demonstrated to have a higher affinity and specificity for tumor cells. In this review, it describes the development of research into active targeted nano-drug delivery systems for lung cancer treatment from the receptors’ or targets’ perspective. We anticipate that this study will help biomedical researchers use nanoparticles (NPs) to treat lung cancer by providing more and novel drug delivery strategies or solid ligands.

The Influences of Surface Charge on the Tumor Targeting of Fe3O4 Nanoparticles for MRI

Nanomedicine based tumor targeting therapy has emerged as a promising strategy to overcome the lack of specificity of conventional chemotherapeutic agents. The “passive” targeting caused by tumor EPR effect and...

The Aggregation Induced Emission Probe of Detecting Enhanced Permeation and Retention Effects is Structured for Evaluating the Applicability of Nanotherapy to Different Tumor Individuals

Enhanced permeation and retention (EPR) effect, the mechanism by which nanodrugs accumulate in tumors and acquire superior curative effect. The questions of these mechanisms occur because of limited clinical transformation of engineered nanomaterials after 30 years. The difference of EPR limits the therapeutic effect of nanodrugs in the individual patient. Evaluation of the EPR effect in the individual patient will aid in selecting patients who will accumulate higher amounts of nanotherapeutics and show better therapeutic efficacy. Based on varied TIMP1/MMP-9 in serum, an aggregation-induced emission luminogen probe was designed and constructed to detect and evaluate the EPR effect in model mouse. The result showed that the ratio of TIMP1/MMP-9 (in the range 0.2–1.2) and fluorescence intensity of the probe were negative linear correlation and the effects of BSA-rhodamine accumulation in tumor were individualized differences as well as correlated with the relative ratio of TIMP-1/MMP-9 in serum. Our data support the development of these biomarkers probes based on the personalized nanotherapy of tumor.

Large-Scale Synthesis of Glutathione-Coated and 68Ga- Labeled Gold Nanoclusters for PET/CT Imaging of Tumors

Gold nanoclusters (AuNCs) have gained popular attention in recent years because of their efficient tumor accumulation through EPR effect and renal clearance. In this work, we put forward a new approach to prepare glutathione-coated, 68Ga-labeled AuNCs (68Ga-GHS@AuNCs) with ultrasmall sizes (< 2 nm) for PET/CT imaging of tumors. GHS@AuNCs has low cytotoxicity in vitro. PET/CT imaging revealed that the 68Ga-GHS@AuNCs could target tumor and be cleared by kidney efficiently. Our study demonstrates that 68Ga-GHS@AuNCs has great potential for detection of tumors.

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible “EPR Effect Enhancer” to Improve Cancer Nanomedicine Efficacy

Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The “enhanced permeability and retention” (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for “EPR enhancers”. Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an “EPR enhancer” of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an “EPR enhancer” in nanomedicine.

Augmented EPR Effect Post IRFA to Enhance the Therapeutic Efficacy of Arsenic Loaded ZIF-8 Nanoparticles on Residual HCC Progression

BackgroundInsufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. ResultsOur data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial-mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo.ConclusionsThis work provides a new paradigm for the treatment of residual HCC after IRFA.

The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application

Chemotherapy for human solid tumors in clinical practice is far from satisfactory. Despite the discovery and synthesis of hundreds of thousands of anticancer compounds targeting various crucial units in cancer cell proliferation and metabolism, the fundamental problem is the lack of targeting delivery of these compounds selectively into solid tumor tissue to maintain an effective concentration level for a certain length of time for drug-tumor interaction to execute anticancer activities. The enhanced permeability and retention effect (EPR effect) describes a universal pathophysiological phenomenon and mechanism in which macromolecular compounds such as albumin and other polymer-conjugated drugs beyond certain sizes (above 40 kDa) can progressively accumulate in the tumor vascularized area and thus achieve targeting delivery and retention of anticancer compounds into solid tumor tissue. Targeting therapy via the EPR effect in clinical practice is not always successful since the strength of the EPR effect varies depending on the type and location of tumors, status of blood perfusion in tumors, and the physical-chemical properties of macromolecular anticancer agents. This review highlights the significance of the concept and mechanism of the EPR effect and discusses methods for better utilizing the EPR effect in developing smarter macromolecular nanomedicine to achieve a satisfactory outcome in clinical applications.

Σύνθεση, χαρακτηρισμός και βιολογική αξιολόγηση νανοδομών επισημασμένων με ραδιοϊσότοπα εκπομπής γ-φωτονίων και ποζιτρονίων

Tην τελευταία δεκαετία, η πρόοδος στον σχεδιασμό ελεγχόμενων συστημάτων μεταφοράς φαρμάκων οδήγησε σε τεράστια ανάπτυξη στη θεραπεία πολλών ασθενειών. Στη μελέτη αυτή ένα είδος σύνθετου νανο-φορέα πυρήνα-κελύφους με μια εσωτερική κοιλότητα σχηματίστηκε με πολυμερισμό γαλακτώματος από μια ποικιλία μονομερών με ειδικές ευαισθησίες. Το μικρό μέγεθος αυτής της δομής επιτρέπει στους νανοφορείς να διαπεράσουν διάφορους βιολογικούς φραγμούς και να επιτύχουν παθητική στόχευση μέσω της επίδρασης ενισχυμένης διαπερατότητας και κατακράτησης (Enhanced Permeability and Retention Effect, EPR effect), η οποία διευκολύνει την απελευθέρωση φαρμάκων ιδιαίτερα στους επιθυμητούς ιστούς χωρίς να προκαλούνται δυσμενείς αντιδράσεις στη θεραπεία των ασθενειών όπως για παράδειγμα στη θεραπεία του καρκίνου. Η συνθετική πορεία αποτελείται από δύο στάδια. Στο πρώτο στάδιο συντίθεται ένας μη τοξικός σφαιρικός πυρήνας και στο δεύτερο στάδιο το κέλυφος σχηματίζεται από ένα συνδυασμό μονομερών. Κάθε μονομερές παρουσιάζει μία μοναδική ευαισθησία όπως pΗ, θερμοκρασιακή και ευαισθησία στο οξειδοαναγωγικό περιβάλλον. Αξιοποιώντας αυτή τη συμπεριφορά και απομακρύνοντας τον πυρήνα, συντέθηκαν νανοδοχεία (NCs) ικανά να ανταποκριθούν σε εξωτερικό ερέθισμα που προκαλεί απελευθέρωση φαρμάκου με ελεγχόμενο τρόπο. Το κύριο πλεονέκτημα αυτής της εργασίας, όσον αφορά τη συνθετική διαδικασία, είναι το εσωτερικό των σφαιρών που διαμορφώθηκε κατά τη διάρκεια του σχηματισμού του κελύφους, επιτρέποντας στα μικρά μόρια, βιολογικού ενδιαφέροντος (αναστολείς), να φιλοξενηθούν και παράλληλα να αποδεσμευτούν στην περιοχή του όγκου. Συμπερασματικά, στην εργασία αυτή, παρουσιάζεται η σύνθεση, ο χαρακτηρισμός αλλά και η βιολογική αξιολόγηση κοίλων νανοδοχείων (ΝCs), με διαφορετικές ευαισθησίες, ως εν δυνάμει συστημάτων μεταφοράς φαρμάκων για τη θεραπεία του καρκίνου ιχνηθετημένα με ραδιενεργά ισότοπα, όπως για παράδειγμα 68Ga και 99mTc.