Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Li HJ

PROVIDER: S-EPMC4839420 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Li Hong-Jun HJ Du Jin-Zhi JZ Du Xiao-Jiao XJ Xu Cong-Fei CF Sun Chun-Yang CY Wang Hong-Xia HX Cao Zhi-Ting ZT Yang Xian-Zhu XZ Zhu Yan-Hua YH Nie Shuming S Wang Jun J

Proceedings of the National Academy of Sciences of the United States of America 20160328 15

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 ...[more]

PMID: 27035960

Similar Datasets

Project description:Tumor-targeting antibody (Ab)-fused cytokines, referred to as immunocytokines, are designed to increase antitumor efficacy and reduce toxicity through the tumor-directed delivery of cytokines. However, the poor localization and intratumoral penetration of immunocytokines, especially in solid tumors, pose a challenge to effectively stimulate antitumor immune cells to kill tumor cells within the tumor microenvironment. Here, we investigated the influence of the tumor antigen-binding kinetics of a murine interleukin 12 (mIL12)-based immunocytokine on tumor localization and diffusive intratumoral penetration, and hence the consequent antitumor activity, by activating effector T cells in immunocompetent mice bearing syngeneic colon tumors. Based on tumor-associated antigen HER2-specific Ab Herceptin (HCT)-fused mIL12 carrying one molecule of mIL12 (HCT-mono-mIL12 immunocytokine), we generated a panel of HCT-mono-mIL12 variants with different affinities (K D) mainly varying in their dissociation rates (k off) for HER2. Systemic administration of HCT-mono-mIL12 required an anti-HER2 affinity above a threshold (K D = 130 nM) for selective localization and antitumor activity to HER2-expressing tumors versus HER2-negative tumors. However, the high affinity (K D = 0.54 or 46 nM) due to the slow k off from HER2 antigen limited the depth of intratumoral penetration of HCT-mono-mIL12 and the consequent tumor infiltration of T cells, resulting in inferior antitumor activity compared with that of HCT-mono-mIL12 with moderate affinity of (K D = 130 nM) and a faster k off. The extent of intratumoral penetration of HCT-mono-mIL12 variants was strongly correlated with their tumor infiltration and intratumoral activation of CD4+ and CD8+ T cells to kill tumor cells. Collectively, our results demonstrate that when developing antitumor immunocytokines, tumor antigen-binding kinetics and affinity of the Ab moiety should be optimized to achieve maximal antitumor efficacy.

Project description:Despite best available therapy, cerebral aspergillosis is an often-lethal complication of disseminated aspergillosis. There is an urgent need to expand the currently limited therapeutic options. In this study, we assessed cerebral drug exposure and efficacy of caspofungin (CAS) using a lethal infant rat model of cerebral aspergillosis. Eleven-day-old Wistar rats were infected by intracisternal injection of Aspergillus fumigatus conidia. Treatment started after 22 h and was continued for 10 days. Regimens were CAS 1 mg/kg/day intraperitoneally (i.p.), liposomal amphotericin B (L-AmB) 5 mg/kg/day i.p., and both drugs combined at the same dose i.p. Infected controls were given NaCl 0.85% i.p. Primary endpoints assessed were survival, cerebral fungal burden, galactomannan index, and drug concentrations in brain homogenate at 2, 3, 5, and 11 days after infection. Compared to those of controls (4.4 ± 2.7 days), survival times were increased by treatment with CAS alone (10.3 ± 1.7 days; P < 0.0001) and CAS combined with L-AmB (9.3 ± 2.8 days; P < 0.0001). In contrast, survival time of L-AmB-treated animals (4.3 ± 3.1 days) was not different from that of controls. Cerebral fungal burden and galactomannan index declined in all animals over time, without significant differences between controls and treated animals. CAS trough levels in brain tissue were between 0.84 and 1.4 μg/g, concentrations we show to be associated with efficacy. AmB trough levels in brain tissue were higher than the MIC of the A. fumigatus isolate. In summary, CAS concentrations in brain tissue suggest it may be therapeutically relevant and it significantly improved survival in this lethal model of cerebral aspergillosis in nonneutropenic rats. The clinical efficacy of CAS treatment for cerebral aspergillosis merits further study. IMPORTANCE Treatment options for cerebral aspergillosis, an often-lethal disease, are limited. The echinocandins (caspofungin is one of them) are not recommended treatment because their brain tissue penetration is often considered insufficient. In a nursing rat model of cerebral aspergillosis that mimics human disease, we found potentially therapeutically relevant concentrations of caspofungin in brain tissue and prolonged survival of caspofungin-treated animals. The efficacy of caspofungin in the treatment of cerebral aspergillosis documented here, if confirmed in other animal models (especially immunosuppressed murine models) and by using additional Aspergillus isolates across a range of CAS minimal effective concentrations (MECs), would suggest that caspofungin merits further study as a treatment option for patients suffering from aspergillosis disseminated to the brain.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets