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.

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Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

Cancers ◽

10.3390/cancers11121855 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1855 ◽

Cited By ~ 29

Author(s):

Lucia Salvioni ◽

Maria Antonietta Rizzuto ◽

Jessica Armida Bertolini ◽

Laura Pandolfi ◽

Miriam Colombo ◽

...

Keyword(s):

Cancer Treatment ◽

Safety Profile ◽

Crucial Role ◽

Clinical Relevance ◽

Scientific Community ◽

Design Development ◽

Manufacturing Costs ◽

Epr Effect ◽

Enhanced Permeability And Retention ◽

Cancer Nanomedicine

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several restrictions, such as high manufacturing costs, technical challenges, and effectiveness below expectations, raised skeptical opinions within the scientific community about the clinical relevance of nanomedicine. In this review, we aim to give an overall vision of the current hurdles encountered by nanotherapeutics along with their design, development, and translation, and we offer a prospective view on possible strategies to overcome such limitations.

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Nanodrug Delivery Systems Modulate Tumor Vessels to Increase the Enhanced Permeability and Retention Effect

Journal of Personalized Medicine ◽

10.3390/jpm11020124 ◽

2021 ◽

Vol 11 (2) ◽

pp. 124

Author(s):

Dong Huang ◽

Lingna Sun ◽

Leaf Huang ◽

Yanzuo Chen

Keyword(s):

Blood Vessels ◽

Tumor Vessels ◽

Epr Effect ◽

Nanodrug Delivery ◽

Enhanced Permeability And Retention ◽

Macromolecular Drugs ◽

Long Time ◽

Vessel Network ◽

Tumor Blood Vessels ◽

The Relationship

The use of nanomedicine for antitumor therapy has been extensively investigated for a long time. Enhanced permeability and retention (EPR) effect-mediated drug delivery is currently regarded as an effective way to bring drugs to tumors, especially macromolecular drugs and drug-loaded pharmaceutical nanocarriers. However, a disordered vessel network, and occluded or embolized tumor blood vessels seriously limit the EPR effect. To augment the EPR effect and improve curative effects, in this review, we focused on the perspective of tumor blood vessels, and analyzed the relationship among abnormal angiogenesis, abnormal vascular structure, irregular blood flow, extensive permeability of tumor vessels, and the EPR effect. In this commentary, nanoparticles including liposomes, micelles, and polymers extravasate through the tumor vasculature, which are based on modulating tumor vessels, to increase the EPR effect, thereby increasing their therapeutic effect.

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Cancer Nanomedicine: A New Era of Successful Targeted Therapy

Journal of Nanomaterials ◽

10.1155/2019/4927312 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Mahmoud Zaki El-Readi ◽

Mohammad Ahmad Althubiti

Keyword(s):

Cancer Treatment ◽

Tumor Targeting ◽

Liposomal Doxorubicin ◽

Polymeric Nanoparticles ◽

New Era ◽

Pathological Characteristics ◽

Cancer Nanomedicine ◽

Approved Drugs ◽

And Function ◽

Care Problems

Cancer is considered as one of the most challenging health care problems. Though there are many approved drugs that can be used for cancer therapy, drug resistance and delivery are among of the barriers of the treatment. In addition, pathological characteristics of tumors and their abnormal blood vessel architecture and function also reduce the efficiency of the conventional cancer treatment. Therefore, looking for techniques that can increase the efficacy of the therapy such as nanoparticles (NPs) is vital. NPs have many properties such as their small size, ability to load various drugs and large surface area, and ability to increase the absorption of conjugated. Therefore, the NPs have been considered as excellent tumor-targeting vehicles. The recent nanoscale vehicles include liposomes, polymeric nanoparticles, magnetic nanoparticles, dendrimers, and nanoshells; lipid-based NPs have been used as conjugates. There are few examples of approved conjugated anticancer NPs including AmBisome® (amphotericin B liposomal) and Doxil® (liposomal doxorubicin). There are many other conjugated anticancer drugs at different stages of clinical trials for treatment of various cancers. This review will discuss the properties of different NPs in cancer treatment and their benefits of overcoming multidrug resistance. In addition, recent advances of using nanomedicine in different approaches of cancer treatment such as chemotherapy, radiotherapy, and immunotherapy will be highlighted in this review.

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Enhanced nanodrug delivery in tumors after near-infrared photoimmunotherapy

Nanophotonics ◽

10.1515/nanoph-2019-0186 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1673-1688 ◽

Cited By ~ 3

Author(s):

Fuyuki F. Inagaki ◽

Aki Furusawa ◽

Peter L. Choyke ◽

Hisataka Kobayashi

Keyword(s):

Near Infrared ◽

Small Molecular Weight ◽

Small Magnitude ◽

Epr Effect ◽

Nanodrug Delivery ◽

Enhanced Permeability And Retention ◽

Naturally Occurring ◽

Limited Success ◽

Effective Manner ◽

Promising Avenue

AbstractTo date, the delivery of nanosized therapeutic agents to cancers largely relies on the enhanced permeability and retention (EPR) effects that are caused by the leaky nature of cancer vasculature. Whereas leaky vessels are often found in mouse xenografts, nanosized agents have demonstrated limited success in humans due to the relatively small magnitude of the EPR effect in naturally occurring cancers. To achieve the superior delivery of nanosized agents, alternate methods of increasing permeability and retention are needed. Near-infrared photoimmunotherapy (NIR-PIT) is a recently reported therapy that relies on an antibody-photon absorber conjugate that binds to tumors and then is activated by light. NIR-PIT causes an increase in nanodrug delivery by up to 24-fold compared to untreated tumors in which only the EPR effect is present. This effect, termed super-EPR (SUPR), can enhance the delivery of a wide variety of nanosized agents, including nanoparticles, antibodies, and protein-binding small-molecular-weight agents into tumors. Therefore, taking advantage of the SUPR effect after NIR-PIT may be a promising avenue to use a wide variety of nanodrugs in a highly effective manner.

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Self-targeted, bacillus-shaped, and controlled-release methotrexate prodrug polymeric nanoparticles for intratumoral administration with improved therapeutic efficacy in tumor-bearing mice

Journal of Materials Chemistry B ◽

10.1039/c5tb00724k ◽

2015 ◽

Vol 3 (39) ◽

pp. 7707-7717 ◽

Cited By ~ 14

Author(s):

Jinyan Lin ◽

Yanxiu Li ◽

Yang Li ◽

Fei Cui ◽

Fei Yu ◽

...

Keyword(s):

Controlled Release ◽

Cancer Chemotherapy ◽

Therapeutic Efficacy ◽

Polymeric Nanoparticles ◽

Intratumoral Administration ◽

Tumor Bearing ◽

Highly Efficient

Self-targeted, bacillus-shaped, and controlled-release methotrexate prodrug polymeric nanoparticles for highly efficient cancer chemotherapy: more elongated is better.

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New Strategy for Controlled Release of Nitric Oxide

Journal of Nano Research ◽

10.4028/www.scientific.net/jnanor.20.61 ◽

2012 ◽

Vol 20 ◽

pp. 61-67 ◽

Cited By ~ 14

Author(s):

Amedea B. Seabra ◽

Priscyla D. Marcato ◽

Larissa B. de Paula ◽

Nelson Durán

Keyword(s):

Nitric Oxide ◽

Vascular Tone ◽

Polymeric Nanoparticles ◽

No Production ◽

Cell Replication ◽

Neuronal Communication ◽

Physiological Processes ◽

Promising Strategy ◽

New Strategy ◽

Metal Organic

Nitric oxide (NO) is involved in several physiological processes, such as the control of vascular tone, the inhibition of platelet aggregation, smooth muscle cell replication, immune response and neuronal communication. Several pathologies have been associated to dysfunctions in the endogenous NO production. Thus, there is a great interest in the development of NO-releasing drugs and in matrices which are able to stabilize and release NO locally in different tissues. In this scenario, the preparation of NO-releasing nanomaterials, such as dendrimers, liposomes, metallic, silica, and polymeric nanoparticles, zeolites and metal organic frameworks, is a promising strategy for delivering NO in diverse applications, as discussed in this work.

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Development of PLGA-Triiodothyronine Nanoparticles for Targeted Delivery in the Cardioprotection Against Ischemic Insult

10.21203/rs.3.rs-746577/v1 ◽

2021 ◽

Author(s):

Ozlem Ozen Karakus ◽

Noureldien H. E. Darwish ◽

Taher Salaheldin ◽

P. C. Taylor Dickinson ◽

Brian Weil ◽

...

Keyword(s):

Targeted Delivery ◽

Hormone Receptors ◽

Polymeric Nanoparticles ◽

Myocardial Damage ◽

Protective Role ◽

Ischemic Heart ◽

H Nmr ◽

New Strategy

Abstract Background: Ischemic heart disease is the main cause of death globally. Cardioprotection is the process whereby mechanisms that reduce myocardial damage, and activate protective factors, contribute to the preservation of the heart. Targeting these processes could be a new strategy in the treatment of post-ischemic heart failure (HF). Triiodothyronine (T3) and thyroxine (T4), which have multiple effects on the heart, prevent myocardial damage. Results: This study describes the formulation, and characterization, of chemically modified polymeric nanoparticles incorporating T3, to target the thyroid hormone receptors. Modified T3 was conjugated to polylactide-co-glycolide (PLGA) to facilitate the active targeting of PLGA-T3. Modified T3 and PLGA-T3 was characterized with 1H-NMR. Protective role of synthesized Phosphocreatine (PCr) encapsulated PLGA-T3 nanoparticles (PLGA-T3/PCr NPs) and PLGA-T3 nanoparticles (PLGA-T3 NPs) in hypoxia-mediated cardiac cell insults were investigated. Conclusions: Data demonstrated that PLGA-T3/PCr NPs represent a potentially new therapeutic for the control of tissue damage in cardiac ischemia and resuscitation.

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From Passive Targeting to Personalized Nanomedicine: Multidimensional Insights on Nanoparticles’ Interaction with the Tumor Microenvironment

Current Pharmaceutical Biotechnology ◽

10.2174/1389201021666201211103856 ◽

2020 ◽

Vol 21 ◽

Author(s):

Aya A. Sebak ◽

Basma M. El-Shenawy ◽

Sara El-Safy ◽

Mohamed El-Shazly

Keyword(s):

Tumor Microenvironment ◽

Protein Corona ◽

Lymphatic Drainage ◽

Biological Macromolecules ◽

Passive Targeting ◽

Epr Effect ◽

The Past ◽

Current Trends ◽

Enhanced Permeability And Retention ◽

Therapeutic Outcomes

: Nanomedicine is revolutionizing the treatment of cancer and has achieved unprecedented outcomes over the past decades. The accumulation of nanoparticles (NPs) in different tumors relies mainly on the enhanced permeability and retention (EPR) effect benefiting from the wide fenestrae of the tumor vasculature and the lack of lymphatic drainage. However, the EPR effect is recognized as a heterogeneous phenomenon resulting in heterogeneous outcomes of clinical trials. Extensive efforts are exerted to enhance the outcomes of nanomedicine in a larger cohort of patients by employing active targeting strategies. However, actively targeted NPs accumulate in tumors by the EPR effect and hence fail to achieve convincing therapeutic outcomes. These obstacles are gradually being removed by improving the understanding of the tumor microenvironment (TME) and the mechanistic interaction of the NPs with its different components. In this review, we provide detailed insights into the past concerns of drug targeting, the current trends of TME reengineering, and the future implications for overcoming past hurdles. Strategies explored in this regard included the use of companion diagnostics and the modulation of the protein corona associated with the systemic administration of NPs and their interaction with biological macromolecules.

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