Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

Lazzari, Gianpiero; Couvreur, Patrick; Mura, Simona

doi:10.1039/c7py00559h

Cited by 157 publications

(136 citation statements)

References 190 publications

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“…To study whether the grafted collagenase on the NPs surface can effectively promote the penetration of NPs in tumors, multicellular spheroids (MCSs) were used for evaluating in vitro penetration. MCSs are more closely related to many key features of the real tumor environment than 2D model, [ 19 ] which can mimic tissue for cell–cell connections and ECM (such as: collagen, proteoglycans, and hyaluronic acid) production. [ 20 ] Therefore, MCSs are an ideal model for evaluating the permeability of NPs in vitro and can provide an important reference for in vivo evaluation.…”

Section: Methodsmentioning

confidence: 99%

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

et al. 2020

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The complex tumor microenvironment constitutes a variety of barriers to prevent nanoparticles (NPs) delivery and results in extremely low accumulation of nanomedicines in solid tumors. Here, a newly developed size-changeable collagenase-modified polymer micelle is employed to enhance the penetration and retention of nanomedicine in deep tumor tissue. The TCPPB micelle is first formed by self-assembly of maleimideterminated poly(ethylene glycol)-block-poly(β-amino ester) (MAL-PEG-PBAE) and succinic anhydride-modified cisplatin-conjugated poly(ε-caprolactone)block-poly(ethylene oxide)-triphenylphosphonium (CDDP-PCL-PEO-TPP). Next, Col-TCPPB NPs are prepared through a "click" chemical combination of thiolated collagenase and maleimide groups on TCPPB micelle. Finally, biocompatible chondroitin sulfate (CS) is coated to obtain CS/Col-TCPPB NPs for avoiding collagenase inactivation in blood circulation. In tumor acidic microenvironment, the hydrophobic PBAE segments of the resultant micelles become hydrophilic, leading to a dissociation and subsequent dissolution of partial collagenase-containing components (Col-PEG-PBAE) from NPs. The dissolved Col-PEG-PBAE promotes the digestion of collagen fibers in tumor tissue like a scavenger, which enhances the NPs penetration. Simultaneously, the increased hydrophilicity of residual Col-PEG-PBAE in the micellar matrix causes an expansion of the NPs, resulting in an enhanced intratumoral retention. In tumor cells, the NPs target to release the cisplatin drugs into mitochondria, achieving an excellent anticancer efficacy.Engineered nanoparticles (NPs), which are capable of improving drug solubility, overcoming pharmacokinetic limitations, and reducing toxic side effects over systemic chemotherapy drugs, perform as a promising nanoplatform for delivering drugs

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Section: Methodsmentioning

confidence: 99%

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

et al. 2020

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“…Anticancer activity in 3D multicellular spheroids 3D multicellular tumor spheroids (MCTSs) are used to simulate the in vivo tumor microenvironment and provide higher complexity than the standard 2D monolayer cultures due to their physiological relevance to solid tumors. [26,27] Therefore, to validate the antitumor activity of the synthesized gold complexes in an in vivo tumore nvironment, cervical cancerc ells (HeLa) were grown in ultra-low attachment (ULA) plates for 2days to generate3 Dm ulticellulars pheroids, which weret hen treated with the IC 50 concentrationsoft he gold complexes. Figure 9s hows the morphological changes in the MCTSs after 72 ho ft reatment with the gold complexes.…”

Section: Interaction With Human Serum Albumin (Hsa)mentioning

confidence: 99%

Potent and Selective Cytotoxic and Anti‐inflammatory Gold(III) Compounds Containing Cyclometalated Phosphine Sulfide Ligands

Reddy

Pooja

Privér

et al. 2019

Chemistry A European J

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Four cycloaurated phosphine sulfide complexes, [Au{k 2 -2-C 6 H 4 P(S)Ph 2 } 2 ][AuX 2 ][ X = Cl (2), Br (3), I( 4)] and [Au{k 2 -2-C 6 H 4 P(S)Ph 2 } 2 ]PF 6 (5), have been prepared and thoroughly characterized. The compounds were found to be stable under physiological-like conditions and showede xcellent cytotoxicity against ab road range of cancerc ell lines and remarkable cytotoxicity in 3D tumor spheroids. Mechanistic studies with cervical cancer( HeLa) cells indicated that the cytotoxic effects of the compounds involve the inhibition of thioredoxin reductasea nd induction of apoptosis through mitochondrial disruption. In vivo experiments in nude mice bearing HeLa xenografts showedt hat treatment with compounds 4 and 5 resulted in significant inhibition of tumorg rowth (35.8 and 46.9 %, respectively), better than that of cisplatin (29 %). The newly synthesized gold complexesw ere also evaluated for their in vitro and in vivo antiinflammatory activity through the study of lipopolysaccharide (LPS)-activated macrophages and carrageenan-induced hind paw edemainr ats, respectively.

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“…Overall, we recreated a functional, microfluidic platform of a 3D tumor microenvironment, with perfusable blood vessel and cancer cells conformed into spheroid, improving the resemblance for the physiological conditions relevant for drug delivery compared to existing models. [29], [30], [32], [33]…”

Section: Scale Bar 50 µMmentioning

confidence: 99%

Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

Feiner‐Gracia

Mares

Buzhor

et al. 2020

Preprint

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The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by confronting different barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix and eventually cancer cell membranes. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is a key factor for the rational design of these systems. One of the key challenges is that current 2D in vitro models do not provide exhaustive information, as they do not fully recapitulate the 3D tumor microenvironment. This deficiency of the 2D models complexity is the main reason for the differences observed in vivo when testing the performance of supramolecular nanocarriers.Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic tumor-on-a-chip. The combination of advanced imaging and a reliable organ-on-a-chip model allow us to track micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation followed during the crossing of barriers by spectral imaging, revealing the interplay between carrier structure, micellar stability and extravasation. Integrating

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Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

Abstract: Application of 3D multicellular tumor spheroids to the investigation of polymer nanomedicines.

Cited by 157 publications

References 190 publications

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

A Size‐Changeable Collagenase‐Modified Nanoscavenger for Increasing Penetration and Retention of Nanomedicine in Deep Tumor Tissue

Potent and Selective Cytotoxic and Anti‐inflammatory Gold(III) Compounds Containing Cyclometalated Phosphine Sulfide Ligands

Real-time Ratiometric Imaging of Micelles Assembly State in a Microfluidic Cancer-on-a-chip

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