Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release

Ruan, Shaobo; Cao, Xi; Cun, Xingli; Hu, Guanlian; Zhou, Yi; Zhang, Yijia; Lu, Libao; He, Qin; Gao, Huile

doi:10.1016/j.biomaterials.2015.05.006

Cited by 259 publications

(179 citation statements)

References 31 publications

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“…It has been validated that the penetration of nanoparticles in tumor space relies heavily on particle size, with the consensus that smaller particles have improved tissue penetration (26,33,44). Such progress has recently inspired interest in developing size-shrinkable anticancer drug delivery systems (15,34,45,46). Compared with previous studies, our strategy has several unique features.…”

Section: Discussionmentioning

confidence: 97%

“…This is particularly important for treating poorly permeable solid tumors, because only the sub-30-nm micelles could penetrate the poorly permeable pancreatic tumors to achieve an antitumor effect (27). For previous systems, their final sizes after shrinkage were still as large as 40-70 nm (34,45,46), which is likely to offset the usefulness of size shrinkage for treating poorly permeable tumors. In our system, the released small PAMAM dendrimer prodrugs have a size of around 5 nm, which is highly potent in penetrating the intractable tumors to reach cancer cells that are far away from the blood vessels.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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

646

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: 97%

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.

646

406

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“…Angiopep-2 has high LRP binding affinity, thus it was a candidate for a dual targeting ligand for NPs to penetrate the BBB and target the brain tumor. Our group conjugated angiopep-2 onto gold NPs (AuNPs) to construct a dual targeting delivery system (Ruan et al 2015c). The model drug, DOX, was anchored onto the AuNPs surface through hydrazone, a pH sensitive linker, which enabled the system to release drug into the tumor and tumor cells in the acidic environment of the tumor.…”

Section: Dual Targeting With One Ligandmentioning

confidence: 99%

Perspectives on Dual Targeting Delivery Systems for Brain Tumors

Gao

2016

J Neuroimmune Pharmacol

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110

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Brain tumor remains one of the most serious threats to human beings. Different from peripheral tumors, drug delivery to brain tumor is largely restricted by the blood brain barrier (BBB). To fully conquer this barrier and specifically deliver drugs to brain tumor, dual targeting delivery systems were explored, which are functionalized with two active targeting ligands: one to the BBB and the other to the brain tumor. The development of dual targeting delivery system is still in its early stage, and attentions need to be paid to issues and concerns that remain unresolved in future studies.

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“…A type of size-shrinkable nanocarrier-based drug delivery system was developed for the inhibition of tumor growth and metastasis, with the capacity of targeting and changing size. 13,14 The prepared NPs could actively target a tumor via receptor-mediated endocytosis, followed by shrinkage from a large size to a small size due to the degradation of the NPs. Current nanomedicine is focused on drug-tethered NPs of relatively larger sizes (.50 nm).…”

Section: Introductionmentioning

confidence: 99%

Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

Bao¹,

Zhang²,

Xu³

et al. 2016

IJN

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Gold nanoparticles (AuNPs) have emerged as a promising anticancer drug delivery scaffold. However, some controversial points still require further investigation before clinical use. A complete understanding of how animal cells interact with drug-conjugated AuNPs of well-defined sizes remains poorly understood. In this study, we prepared a series of 10-hydroxycamptothecin (HCPT)-AuNP conjugates of different sizes and compared their cytotoxic effect in vitro and antitumor effect in vivo. Transmission electron micrographs showed that the NPs had a round, regular shape with a mean diameter of ~10, 25, and 50 nm. An in vitro drug release study showed that HCPT was continuously released for 120 hours. HCPT-AuNPs showed greater cytotoxic effects on the MDA-MB-231 cell line compared with an equal dose of free HCPT. Notably, HCPT-AuNPs of an average diameter of 50 nm (HCPT-AuNPs-50) had the greatest effect. Furthermore, administration of HCPT-AuNPs-50 showed the most tumor-suppressing activity against MDA-MB-231 tumor in mice among all treatment groups. The results indicate that AuNPs not only act as a carrier but also play an active role in mediating biological effects. This work gives important insights into the design of nanoscale delivery and therapeutic systems.

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Matrix metalloproteinase-sensitive size-shrinkable nanoparticles for deep tumor penetration and pH triggered doxorubicin release

Cited by 259 publications

References 31 publications

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

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

Perspectives on Dual Targeting Delivery Systems for Brain Tumors

Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies

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