Intratumor Heterogeneity and Its Impact on Drug Distribution and Sensitivity

Nerini, Ilaria Fuso; Morosi, Lavinia; Zucchetti, Massimo; Ballerini, Andrea; Giavazzi, Raffaella; D’Incalci, Maurizio

doi:10.1038/clpt.2014.105

Cited by 62 publications

(53 citation statements)

References 68 publications

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“…Major challenges with conventional cancer therapy are poor drug efficacy and extensive toxicity to non-cancerous tissues. In particular, achieving effective drug concentration within a tumor is impeded by the low solubility of hydrophobic chemotherapeutics and transport barriers caused by the complex physiology of tumors [1]. Additionally, classical chemotherapeutics nonspecifically attack all actively dividing cells, leading to systemic toxicity and undesirable side effects.…”

Section: Introductionmentioning

confidence: 99%

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Huang

Rollett

Kaplan

2014

Expert Opinion on Drug Delivery

116

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Introduction Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure-function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semicrystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli responsive properties and tenability, thereby, becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release. Areas covered An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties, and self-assembly mechanisms are discussed. The review focuses on sequence-structure-function relationships, stimuli responsive features, and current and potential drug delivery applications. Expert opinion The tunable material properties allow SELPs to be pursued as promising biomaterials for nano-carriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.

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Section: Introductionmentioning

confidence: 99%

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Huang

Rollett

Kaplan

2014

Expert Opinion on Drug Delivery

116

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“…The ability of a molecule to penetrate neoplastic tissue depends on its own physicochemical properties but also on the tumor vascularization and interstitial pressure which depend not only on cancer cell growth but also on the tumor microenvironment34. This microenvironment has a poorly organized vasculature that permits the formation of hypoxic areas with increased interstitial fluid pressure, so they are hard to reach for chemotherapeutic drugs56.…”

mentioning

confidence: 99%

3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors

Giordano

Morosi

Veglianese

et al. 2016

Sci Rep

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Mass Spectrometry Imaging (MSI) is a widespread technique used to qualitatively describe in two dimensions the distribution of endogenous or exogenous compounds within tissue sections. Absolute quantification of drugs using MSI is a recent challenge that just in the last years has started to be addressed. Starting from a two dimensional MSI protocol, we developed a three-dimensional pipeline to study drug penetration in tumors and to develop a new drug quantification method by MALDI MSI. Paclitaxel distribution and concentration in different tumors were measured in a 3D model of Malignant Pleural Mesothelioma (MPM), which is known to be a very heterogeneous neoplasm, highly resistant to different drugs. The 3D computational reconstruction allows an accurate description of tumor PTX penetration, adding information about the heterogeneity of tumor drug distribution due to the complex microenvironment. The use of an internal standard, homogenously sprayed on tissue slices, ensures quantitative results that are similar to those obtained using HPLC. The 3D model gives important information about the drug concentration in different tumor sub-volumes and shows that the great part of each tumor is not reached by the drug, suggesting the concept of pseudo-resistance as a further explanation for ineffective therapies and tumors relapse.

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“…Abnormal stroma is thought to induce chemoresistance (5)(6)(7)(8). Renormalization caused by agents targeting the stroma would resensitize the tumor to chemotherapy through various mechanisms, including increased chemotherapy delivery to the interstitium, decreased hypoxia, or recovery of the antitumor immune response (5,9,10).…”

Section: Introductionmentioning

confidence: 99%

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

Quintela‐Fandino

Lluch

Manso

et al. 2017

Clinical Cancer Research

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Purpose: We previously detected promising efficacy of neoadjuvant nintedanib (a multityrosine kinase inhibitor, TKI) in early HER2-negative breast cancer. In a preclinical study, we monitored stromal hypoxia with 18 F-fluoromisonidazole-positron emission tomography (18F-FMISO-PET); we found that reoxygenation of tumors (or lack of it) during a window-ofopportunity (WoO) treatment with TKIs correlated with the benefit (or lack of it) from TKI-plus-chemotherapy combinations. We studied the predictive role of 18F-FMISO-PET for the TKI nintedanib in the neoadjuvant setting in a phase II WoO randomized trial.Experimental Design: Patients were randomized to a 14-day WoO of nintedanib preceded and followed by an 18F-FMISO-PET, followed by nintedanib plus weekly paclitaxel (Arm A) or an 18F-FMISO-PET followed by weekly paclitaxel (Arm B) before surgery. The endpoint was residual cancer burden (RCB). The objective was to detect the patients with no response (RCB-III) on the basis of the baseline or evolutive 18F-FMISO-PET values/ changes.Results: One-hundred and thirty HER2-negative patients were randomized. Seventeen (27.9%), 34 (55.7%), and 8 (13.1%) patients had an RCB of III, II, and I/0, respectively, in Arm A. In this arm, baseline hypoxic tumors had a 4.4-fold higher chance of experiencing RCB ¼ 3 (P ¼ 0.036) compared with baseline normoxic tumors. Nintedanib WoO induced tumor reoxygenation in 24.5% of the patients; those not reoxygenating showed a trend toward higher chance of experiencing RCB-III (6.4-fold; P ¼ 0.09). In Arm B, 18F-FMISO-PET lacked predictive/ prognostic value.Conclusions: Baseline hypoxic tumors (measured with 18F-FMISO-PET) do not benefit from neoadjuvant nintedanib.

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Intratumor Heterogeneity and Its Impact on Drug Distribution and Sensitivity

Cited by 62 publications

References 68 publications

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics

3D Mass Spectrometry Imaging Reveals a Very Heterogeneous Drug Distribution in Tumors

18F-fluoromisonidazole PET and Activity of Neoadjuvant Nintedanib in Early HER2-Negative Breast Cancer: A Window-of-Opportunity Randomized Trial

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