A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals

Wang, Yiguang; Zhou, Kejin; Huang, Gang; Hensley, Christopher T.; Huang, Xiaonan; Ma, Xinpeng; Zhao, Tian; Sumer, Baran D.; DeBerardinis, Ralph J.; Gao, Jinming

doi:10.1038/nmat3819

Cited by 707 publications

(580 citation statements)

References 35 publications

(37 reference statements)

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“…Second, the stimuli that were used to trigger size shrinkage previously were either by enzyme or UV light, whose applicability, to a certain extent, would be restricted to only a subset of cancer types owing to either the heterogeneous expression levels of target enzymes in a specific cancer type or the superficial penetration depth of UV light (14). In contrast, we used acidic extracellular pH, a more general hallmark of the microenvironment of most solid tumors (36,48), as the stimulus to activate the release of small particles at tumor sites. This endows our strategy with much broader specificity and applicability, which has been partially justified by the superior antitumor activities in multiple tumor models.…”

Section: Discussionmentioning

confidence: 99%

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

647

406

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A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.nanomedicine | particle size | tumor penetration | tumor extracellular pH | stimuli responsive

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Section: Discussionmentioning

confidence: 99%

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

647

406

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“…30 Previous studies reported that hypoxic regions in the tumors are more acidic. 31 Thus, the abovementioned pH-responsive liposomes can obtain the surface positive charge density under tumor hypoxic conditions and will improve the uptake efficiency by tumor cells. It has been demonstrated that the nitro group of nitroimidazoles can be converted to an amino group through a series of selective bioreductions under hypoxic conditions.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-responsive ionizable liposome delivery siRNA for glioma therapy

Liu¹,

Zhang²,

Xie³

et al. 2017

IJN

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Here, we report the hypoxia-responsive ionizable liposomes to deliver small interference RNA (siRNA) anticancer drugs, which can selectively enhance cellular uptake of the siRNA under hypoxic and low-pH conditions to cure glioma. For this purpose, malate dehydrogenase lipid molecules were synthesized, which contain nitroimidazole groups that impart hypoxia sensitivity and specificity as hydrophobic tails, and tertiary amines as hydrophilic head groups. These malate dehydrogenase molecules, together with DSPE-PEG2000 and cholesterol, were self-assembled into O′ 1 ,O 1 -(3-(dimethylamino)propane-1,2-diyl) 16-bis(2-(2-methyl-5-nitro-1 H -imidazol-1-yl)ethyl) di(hexadecanedioate) liposomes (MLP) to encapsulate siRNA through electrostatic interaction. Our study showed that the MLP could deliver polo-like kinase 1 siRNA (siPLK1) into glioma cells and effectively enhance the cellular uptake of MLP/siPLK1 because of increased positive charges induced by hypoxia and low pH. Moreover, MLP/siPLK1 was shown to be very effective in inhibiting the growth of glioma cells both in vitro and in vivo. Therefore, the MLP is a promising siRNA delivery system for tumor therapy.

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“…In parallel, nanomaterials have been developed as probes for fluorescent, optical, Raman, and magnetic resonance imaging of the tumor (20-23). The use of dual-emissive materials or stimuli-responsive nanomaterials has further advanced the imaging modality to the molecular level by conferring the ability to monitor subcellular and microenvironment changes, such as hypoxia or pH transitions (24,25). Similarly, tumor-activatable nanoparticles were used to detect metastasis and residual tumor (26).…”

mentioning

confidence: 99%

Reporter nanoparticle that monitors its anticancer efficacy in real time

Kulkarni

Rao

Natarajan

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The ability to monitor the efficacy of an anticancer treatment in real time can have a critical effect on the outcome. Currently, clinical readouts of efficacy rely on indirect or anatomic measurements, which occur over prolonged time scales postchemotherapy or postimmunotherapy and may not be concordant with the actual effect. Here we describe the biology-inspired engineering of a simple 2-in-1 reporter nanoparticle that not only delivers a cytotoxic or an immunotherapy payload to the tumor but also reports back on the efficacy in real time. The reporter nanoparticles are engineered from a novel two-staged stimuli-responsive polymeric material with an optimal ratio of an enzyme-cleavable drug or immunotherapy (effector elements) and a drug function-activatable reporter element. The spatiotemporally constrained delivery of the effector and the reporter elements in a single nanoparticle produces maximum signal enhancement due to the availability of the reporter element in the same cell as the drug, thereby effectively capturing the temporal apoptosis process. Using chemotherapy-sensitive and chemotherapy-resistant tumors in vivo, we show that the reporter nanoparticles can provide a real-time noninvasive readout of tumor response to chemotherapy. The reporter nanoparticle can also monitor the efficacy of immune checkpoint inhibition in melanoma. The self-reporting capability, for the first time to our knowledge, captures an anticancer nanoparticle in action in vivo.T he failure of anticancer therapy is a major cause of mortality (1). Although the current dogma underlying resistance is based on the Darwinian selection of mutations acquired over time under chemotherapy pressure, emerging evidence indicates that anticancer drugs can be rendered ineffective early on by intrinsic or adaptive resistance as a function of tumor heterogeneity (2-4). For example, response rates to first-line chemotherapy treatments in metastatic breast cancer patients range from a dismal 30% to 70%, and patients with disease progression need to be switched to a different drug (5). Similarly, about 40-60% of patients with a wild-type KRAS do not respond to cetuximab (6). The ability to detect early whether a treatment is working or not and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life (7,8).Currently, tumor response to therapy is determined using techniques for direct anatomical measurements, such as computed tomography (CT) and magnetic resonance imaging, or indirectly using positron emission tomography with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG-PET) to quantify metabolic activity. However, these techniques lack the sensitivity or specificity to enable very early response assessment, and often, clinicopathological and metabolic readouts can be discordant (5, 9, 10). In the case of immunotherapy, for example, a productive immune response (T cell infiltration) and the unimpeded growth of the tumor will both be manifest as progression on the conventional ...

show abstract

A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals

Cited by 707 publications

References 35 publications

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy

Hypoxia-responsive ionizable liposome delivery siRNA for glioma therapy

Reporter nanoparticle that monitors its anticancer efficacy in real time

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