Small-sized polymeric micelles incorporating docetaxel suppress distant metastases in the clinically-relevant 4T1 mouse breast cancer model

Li, Yunfei; Jin, Mingji; Shao, Shuai; Huang, Wei; Yang, Feifei; Chen, Wei; Zhang, Shenghua; Xia, Guimin; Gao, Zhonggao

doi:10.1186/1471-2407-14-329

Cited by 38 publications

(21 citation statements)

References 47 publications

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“…The release profile of DTX from HPG-C 10 -HPG is consistent with the proposed "three-region" model. 32 33 A survey of recently reported polymeric micelle formulation of DTX reveals that most of the polymeric NP releases 50% of the incorporated DTX within 5-15 h, [34][35][36][37][38] comparatively much faster than the release from HPG-C 10 -HPG. However, there are polymeric micelles that release DTX with much slower kinetics.…”

Section: Discussionmentioning

confidence: 99%

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Wong¹,

Misri²,

Shenoi³

et al. 2016

j biomed nanotechnol

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PEGylation is commonly used to increase the plasma residence time of anticancer drug nanocarriers. However, PEGylation may trigger antibody production and lead to accelerated blood clearance in subsequent administrations. Moreover, the presence of PEG shells on nanocarriers may also hamper endosomal escape and decrease drug payload release. To avoid these shortcomings, we synthesized and evaluated a non-PEGylated, hyperbranched polyglycerol nanoparticle (HPG NP) with a hydrophobic core and a hydrophilic HPG shell, HPG-C10-HPG, as a candidate for systemic delivery of anticancer drug. In vitro studies with primary human cell lines revealed that HPG-C10-HPG possesses low cytotoxicity. The presence of long chain alkyl groups (C1o) in the core as the hydrophobic pocket in the NP enabled the binding and sustained release of the hydrophobic drug docetaxel. Remarkably, the docetaxel-loaded HPG-C10-HPG formulation also confers preferential protection to primary cells, when compared to cancer cells, potentially widening the therapeutic index. HPG-C10-HPG, however, accumulated at higher levels in the liver and spleen when administered intravenously in mice. Comparing the biodistribution patterns of HPG-C10-HPG, PEGylated HPG-C10-PEG, and unmodified HPG in a xenograft model reveals that the accumulation pattern of HPG-C10-HPG was attributed to insufficient shielding of the hydrophobic groups by the HPG shell. Our results revealed the influence of the nature of the hydrophilic shell and the presence of hydrophobic groups on the tumor-to-tissue accumulation specificities of these HPG NP variants. Therefore, the present study provides insights into the structural considerations of future HPG NP designs for systemic drug delivery.

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Section: Discussionmentioning

confidence: 99%

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Wong¹,

Misri²,

Shenoi³

et al. 2016

j biomed nanotechnol

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“…Apoptotic cells were determined by dual staining with an Annexin V and propidium iodide (PI) kit (4A Biotech) according to the manufacturer's instructions (33). After 48 h of incubation in the exponential stage, A549 cells seeded in 12-well plates were treated for a further 48 h with 10 nmol/ml Aisu, DANPs and PEG-DANPs, respectively.…”

Section: Methodsmentioning

confidence: 99%

A comparative study on the effect of docetaxel-albumin nanoparticles and docetaxel-loaded PEG-albumin nanoparticles against non-small cell lung cancer

Gao¹,

Jin²,

Yin³

et al. 2015

International Journal of Oncology

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Abstract. The present study mainly compared the effect of docetaxel-albumin nanoparticles (DANPs) and docetaxelloaded PEG-albumin nanoparticles (PEG-DANPs) against non-small cell lung cancer (NSCLC). We made systematic assessments on these three drugs against NSCLC both in vitro and in vivo. With the purpose of eliminating side-effects of the commercial formulation (Tween-80) and prolonging the blood circulation time, we used emulsion-evaporation crosslink method to prepare DANPs and PEG-DANPs. The DANPs had an average particle size of 163.4±3.76 nm, a zeta potential of -19.4±0.18 mV, a polydispersity index of 0.143±0.03, a drug loading of 8.71±0.98%, and an encapsulation efficiency of 93.58±0.86%; the average particle size of PEG-DANPs is 169.19±2.36 nm, zeta potential is -18.2±0.21 mV, with a polydispersity index of 1.56±0.05, a drug loading of 8.72±1.05% and an encapsulation efficiency of 95.4±5.5%. PEG-DANPs showed a dose-and time-dependent efficacy in cytotoxicity studies in vitro; the hemolysis test indicated that PEG-DANPs had less hemocytolysis than Aisu ® and DANPs; in addition, a more prolonged circulation time and sustained in vitro release behavior were observed in the PEG-DANPs compared with Aisu ® and DANPs; the cellular uptake test in vitro demonstrated that PEG-DANPs could be absorbed easier into the nucleus; furthermore, the tumor growth of NSCLC-bearing nude mice in vivo was reduced the most by PEG-DANPs. In conclusion, the PEG-DANPs have the lowest side-effects, the highest antitumor activity with the longest blood circulation time of the three drugs, and it will provide an alternative to patients with NSCLC. IntroductionLung cancer is a very common malignant tumor with incidence and mortality rates the first worldwide, almost one million patients are diagnosed with lung cancer each year all over the world. NSCLC accounts for 75-85% among the total number of lung cancer, and elderly patients aged >65 years accounted for >50% (1). It is always at the late stage when patients were discovered (stage III or IV) and the 5-year survival rate is only 12-15% (2,3), thus, these patients cannot receive surgical treatment (4,5).For elderly advanced NSCLC patients, chemotherapy is still the first choice of treatment (6,7), it is a relatively effective treatment for elderly NSCLC patients who cannot tolerant surgical operation. It can effectively reduce the progress of lung cancer and the recurrence, enhance the effect of clinical treatment, prolong patient survival rate and improve their quality of life (8).There are some chemotherapy regimens and drugs for elderly NSCLC patients, such as cisplatin, VP-16, gemcitabine, paclitaxel and docetaxel (9). However, there is lack of a mature and effective way for NSCLC because most of the elderly patients refuse or are unable to complete the treatment. So how to choose a drug with good effect and little side reaction is a hot spot in tumor research (10,11). Docetaxel is a cell cycle specific antitumor drug which is applied to cells at the M phase. It is a relative...

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“…The combination therapy ratio of DTX and tranilast was set at 1:20 (mol/mol) according to previous researches. 39,40 The addition of tranilast in a 20-fold mole ratio of free DTX or DTX-Ms (1.25-20 µM) stimulated greater cytotoxicity (Figure 2A), revealing tranilast's synergistic effect on antitumor cell proliferation.…”

Section: Preparation and Characterization Of Dtx-loaded Micellesmentioning

confidence: 99%

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

Pang¹,

Li²,

Sun³

et al. 2018

IJN

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BackgroundAbnormal expression of stromal cells and extracellular matrix in tumor stroma creates a tight barrier, leading to insufficient extravasation and penetration of therapeutic agents. Cancer-associated fibroblasts (CAFs) take on pivotal roles encouraging tumor progression.MethodTo surmount the refractoriness of stroma, we constructed a multi-targeting combined scenario of anti-CAFs agent tranilast and antitumor agent docetaxel micelles (DTX-Ms). Tranilast cut down crosstalk between tumor cells and stromal cells, ameliorated the tumor microenvironment, and enhanced the antiproliferation efficacy of DTX-Ms on cancer cells.ResultsDiverse experiments demonstrated that tranilast enhanced DTX-Ms’ antitumor effect in a two-stage pattern by CAFs ablation, tumor cell migration blocking, and metastasis inhibition. Along with activated CAFs decreasing in vivo, the two-stage therapy succeeded in reducing interstitial fluid pressure, normalizing microvessels, improving micelles penetration and retention, and inhibiting tumor growth and metastasis. Interestingly, tranilast alone failed to inhibit tumor growth in vivo, and it could only be used as an adjuvant medicine together with an antitumor agent.ConclusionOur proposed two-stage therapy offers a promising strategy to enhance antitumor effects by breaking down CAFs barrier and increasing micellar delivery efficiency.

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Small-sized polymeric micelles incorporating docetaxel suppress distant metastases in the clinically-relevant 4T1 mouse breast cancer model

Cited by 38 publications

References 47 publications

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

Design Considerations for Developing Hyperbranched Polyglycerol Nanoparticles as Systemic Drug Carriers

A comparative study on the effect of docetaxel-albumin nanoparticles and docetaxel-loaded PEG-albumin nanoparticles against non-small cell lung cancer

Prior anti-CAFs break down the CAFs barrier and improve accumulation of docetaxel micelles in tumor

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