Parameters Affecting the Enhanced Permeability and Retention Effect: The Need for Patient Selection

Natfji, Az Alddien; Ravishankar, Divyashree; Osborn, Helen M. I.; Greco, Francesca

doi:10.1016/j.xphs.2017.06.019

Cited by 108 publications

(80 citation statements)

References 72 publications

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“…Indeed, sufficiently small nanoparticles (<200 nm) would cross the hyperpermeable tumor blood vessels (enhanced permeability) and accumulate within the tumor parenchyma due to the lack of lymphatic drainage (retention). However, clinical and pre-clinical studies are starting to demonstrate the significant variability of the EPR effect within patients and along the overall development of the disease (Natfji et al, 2017). As such, relying exclusively on the EPR effect to reach the malignant tissue may not always be a successful strategy.…”

Section: Introductionmentioning

confidence: 99%

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells

Ferreira

Rizzuti

Palange

et al. 2020

Front. Bioeng. Biotechnol.

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Fine-tuning loading and release of therapeutic and imaging agents associated with polymeric matrices is a fundamental step in the preclinical development of novel nanomedicines. Here, 1,000 × 400 nm Discoidal Polymeric Nanoconstructs (DPNs) were realized via a top-down, template-based fabrication approach, mixing together poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol)-diacrylate (PEG-DA) chains in a single polymer paste. Two different loading strategies were tested, namely the "direct loading" and the "absorption loading." In the first case, the agent was directly mixed with the polymeric paste to realize DPNs whereas, in the second case, DPNs were first lyophilized and then rehydrated upon exposure to a concentrated aqueous solution of the agent. Under these two loading conditions, the encapsulation efficiencies and release profiles of different agents were systematically assessed. Specifically, six agents were realized by conjugating lipid chains (DSPE) or polymeric chains (PEG) to the near-infrared imaging molecule Cy5 (DSPE-Cy5 A and DSPE-Cy5 B); the chemotherapeutic molecules methotrexate (DSPE-MTX and PEG-MTX) and doxorubicin (LA-DOX and DSPE-DOX). Moderately hydrophobic compounds with low molecular weights (MW) returned encapsulation efficiencies as high as 80% for the absorption loading. In general, direct loading was associated with encapsulation efficiencies lower than 1%. The agent hydrophobicity and MW were shown to be critical also in tailoring the release profiles from DPNs. On triple-negative breast cancer cells (MDA-MB-231), absorption loaded DOX-DPNs showed cytotoxic activities comparable to free DOX but slightly delayed in time. Preliminary in vivo studies demonstrated the high stability of Cy5-DPNs. Collectively, these results demonstrate that the pharmacological properties of DPNs can be finely optimized by changing the loading strategies (direct vs. absorption) and compound attributes (hydrophobicity and molecular weight).

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Section: Introductionmentioning

confidence: 99%

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells

Ferreira

Rizzuti

Palange

et al. 2020

Front. Bioeng. Biotechnol.

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“…The most pronounced EPR effect was observed in pancreatic, colon, breast, and stomach cancers. Also, a higher accumulation of nanoparticles was found in larger tumors [39].…”

Section: Synthetic Nanocarriersmentioning

confidence: 88%

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

2018

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Since the discovery of cisplatin and its potency in anticancer therapy, the development of metallodrugs has been an active area of research. The large choice of transition metals, oxidation states, coordinating ligands, and different geometries, allows for the design of metal-based agents with unique mechanisms of action. Many metallodrugs, such as titanium, ruthenium, gallium, tin, gold, and copper-based complexes have been found to have anticancer activities. However, biological application of these agents necessitates aqueous solubility and low systemic toxicity. This minireview highlights the emerging strategies to facilitate the in vivo application of metallodrugs, aimed at enhancing their solubility and bioavailability, as well as improving their delivery to tumor tissues. The focus is on encapsulating the metal-based complexes into nanocarriers or coupling to biomacromolecules, generating efficacious anticancer therapies. The delivery systems for complexes of platinum, ruthenium, copper, and iron are discussed with most recent examples. explored as possible alternatives, but none have yet entered the clinic. Importantly, high efficacy of platinum paved the way for the development of other transition metal complexes, many with outstanding cytotoxic properties against cancer cells.Transition metals form complexes of multiple geometries based on the number of coordination sites, offering a stereoisomeric diversity higher than carbon. In addition, a synthesis of metallodrugs requires fewer steps when compared to organic compounds. This is accompanied by a myriad choice of coordinating ligands [17] facilitating fine-tuning the properties of metal-based complexes [17,18]. The octahedral titanium species cis-diethoxy-bis(1-phenylbutane-1,3-dionato)titanium(IV) [(bzac) 2 Ti(OEt) 2 ] (budotitane), was the first non-Pt(II) metal compound that reached clinical trials [19]. Following this, ruthenium-based complexes were explored showing fewer side effects when compared to platinum-based agents and activity against Pt-resistant cancers [20][21][22]. Two ruthenium derivates, imidazolium trans-DMSO-imidazole-tetrachlororuthenate (NAMI-A) and imidazolium trans-[tetrachlorido(DMSO)(1H-imidazole)ruthenate(III)] (KP-1019), have been tested in clinical trials [22,23]. KP-1019 showed efficacy towards primary tumors, such as colon cancer, without triggering systemic toxicity, while NAMI-A was not cytotoxic but demonstrated activity against metastases. Moreover, NKP-1339 (the sodium salt analogue of KP1019, sodium trans-[tetrachloridobis(1H-indazole)ruthenate(III)]) has successfully completed a phase I clinical trial [24]. NKP-1339 is Ru(III) that binds to serum proteins albumin and transferrin, which transport and deliver the metallodrug to the tumor tissue. Once inside endosomes, NKP-1339 reduces to Ru(II). Recently, new designs of ruthenium complexes are emerging that include Ru(η 5 -C 5 H 5 ) core. This class of Ru(II) compounds demonstrates enhanced selectivity and effectiveness, for example ruthenium pyridocarbazole (DW1/2...

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“…The magnitude of the EPR effect in humans highly depends on the particularities of the patient and the tumor [113] although some alternative strategies, such as tumor-homing peptides or some types of cells, are currently being explored to overcome the lack of EPR effect.…”

Section: Nanotechnology For Cancer Treatmentmentioning

confidence: 99%

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

2020

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Bone diseases, such as bone cancer, bone infection and osteoporosis, constitute a major issue for modern societies as a consequence of their progressive ageing. Even though these pathologies can be currently treated in the clinic, some of those treatments present drawbacks that may lead to severe complications. For instance, chemotherapy lacks great tumor tissue selectivity, affecting healthy and diseased tissues. In addition, the inappropriate use of antimicrobials is leading to the appearance of drug-resistant bacteria and persistent biofilms, rendering current antibiotics useless. Furthermore, current antiosteoporotic treatments present many side effects as a consequence of their poor bioavailability and the need to use higher doses. In view of the existing evidence, the encapsulation and selective delivery to the diseased tissues of the different therapeutic compounds seem highly convenient. In this sense, silica-based mesoporous nanoparticles offer great loading capacity within their pores, the possibility of modifying the surface to target the particles to the malignant areas and great biocompatibility. This manuscript is intended to be a comprehensive review of the available literature on complex bone diseases treated with silica-based mesoporous nanoparticles—the further development of which and eventual translation into the clinic could bring significant benefits for our future society.

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Parameters Affecting the Enhanced Permeability and Retention Effect: The Need for Patient Selection

Cited by 108 publications

References 72 publications

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells

Optimizing the Pharmacological Properties of Discoidal Polymeric Nanoconstructs Against Triple-Negative Breast Cancer Cells

Nano-Based Systems and Biomacromolecules as Carriers for Metallodrugs in Anticancer Therapy

Mesoporous Silica Nanoparticles for the Treatment of Complex Bone Diseases: Bone Cancer, Bone Infection and Osteoporosis

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