Specific drug delivery efficiently induced human breast tumor regression using a lipoplex by non-covalent association with anti-tumor antibodies

Lin, Yuling; Tsai, Nu‐Man; Chen, Chia-Hung; Liu, Yen Ku; Lee, Chung‐Jen; Chan, Yi Lin; Wang, Yu Shan; Chang, Yuan; Lin, Chi Hsin; Huang, Tse-Hung; Wang, Chao Ching; Hwa, Kwan; Liao, Kuang‐Wen

doi:10.1186/s12951-019-0457-3

Cited by 31 publications

(30 citation statements)

References 26 publications

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“…20,22,23 The properties of LPPCs allow them to strongly capture antigens or immunomodulators on their surfaces and be used as an adjuvant to trigger Th2 immune responses and antibody class switch. 24 LPPCs also strongly captured antibodies for specific drug delivery 25 and captures proteins for intracellular protein therapy. 26 In our previous study, LPPC was shown to protect BP structure against protein adsorption in the blood to preserve the drug's stability and cytotoxicity during transportation.…”

Section: Introductionmentioning

confidence: 99%

Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma

Lin¹,

Huang²,

Chang³

et al. 2020

IJN

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Background: n-Butylidenephthalide (BP) has anti-tumor effects on glioblastoma. However, the limitation of BP for clinical application is its unstable structure. A polycationic liposomal polyethylenimine (PEI) and polyethylene glycol (PEG) complex (LPPC) has been developed to encapsulate BP for drug structure protection. The purpose of this study was to investigate the anti-cancer effects of the BP/LPPC complex on glioblastoma in vitro and in vivo. Methods: DBTRG-05MG tumor bearing xenograft mice were treated with BP and BP/ LPPC and then their tumor sizes, survival, drug biodistribution were measured. RG2 tumor bearing F344 rats also treated with BP and BP/LPPC and then their tumor sizes by magnetic resonance imaging for evaluation blood-brain barrier (BBB) across and drug therapeutic effects. After treated with BP/LPPC in vitro, cell uptake, cell cycle and apoptotic regulators were analyzed for evaluation the therapeutic mechanism. Results: In athymic mice, BP/LPPC could efficiently suppress tumor growth and prolong survival. In F334 rats, BP/LPPC crossed the BBB and led to tumor shrinkage. BP/LPPC promoted cell cycle arrest at the G 0 /G 1 phase and triggered the extrinsic and intrinsic cell apoptosis pathways resulting cell death. BP/LPPC also efficiently suppressed VEGF, VEGFR1, VEGFR2, MMP2 and MMP9 expression. Conclusion: BP/LPPC was rapidly and efficiently transported to the tumor area across the BBB and induced cell apoptosis, anti-angiogenetic and anti-metastatic effects in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Encapsulated n-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma

Lin¹,

Huang²,

Chang³

et al. 2020

IJN

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“…TZB modified NPs were effectively internalized and distributed near the nucleus within HER2-positive cancer cells 16 . Furthermore, in vivo studies revealed that TZB decorated liposome-PEG-PEI complex (LPPC) improved the site specific delivery of docetaxel-loaded LPPC to the tumor area but not to the healthy organs 17 . In addition, designing the NPs in the size range of 100-200 nm while applying a camouflaged surface coating, passive accumulation of these nanocarriers, resulting from their long circulation and enhanced permeation and retention, will synergize their active targeting 18 .…”

mentioning

confidence: 99%

Near IR responsive targeted integrated lipid polymer nanoconstruct for enhanced magnolol cytotoxicity in breast cancer

Elhabak

Osman

Mohamed

et al. 2020

Sci Rep

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Advances in cancer nanotechnology aim at improving specificity and effectiveness for tumor treatment. Amalgamation of different treatment modalities is expected to provide better cancer combating. Herein, We developed a long circulating nanocarrier comprising trastuzumab (TZB) surface modified polylactic-co-glycolic acid (pLGA) nanoparticles (nps) co-encapsulating magnolol (Mag) and gold nanoparticles (GNPs). A modified single step nanoprecipitation method was adopted ensuring particle coating with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) while co-encapsulating Gnps. tZB was then anchored on nps surface using a carbodiimide chemistry. the cytotoxicity of the developed system was evaluated with and without photothermal irradiation. nps cellular uptake was then followed using confocal microscopical imaging. A hybrid matrix composed of pLGA/tpGS and surface decorated with TZB with a conjugation efficiency of ˃65%, was confirmed via ftiR, 1 HnMR. Gnps could only be included in the nps, when placed in the organic phase as evidenced by the shifted GNPs surface plasmonic resonance and confirmed via imaging coupled with energy dispersive X-ray analysis. Optimized NPs (136.1 ± 1.3 nm, −8.2 ± 1 mV and Mag encapsulation efficiency of 81.4 ± 1.8%) were able to boost Mag cytotoxicity on breast cancer cells while providing a selective multifunctional therapy with an added photothermal effect. Despite the great advances in cancer research, breast cancer remains one of the most challenging diseases risking the lives of a considerable proportion of women world wide 1. Lack of selectivity, poor drug penetration in solid tumors, multi drug resistance (MDR) with increased cells sensitivity added to the drug systemic side effects, represent some of the major barriers for a successful therapy 2. Smart drug delivery systems incorporating different cancer targeting approaches including: passive, active and stimuli responsive had been suggested to improve outcomes of cancer treatment 3,4. In this study, we focused on integrating many strategies that could potentiate the effect of a natural cytotoxic drug with potential activity against breast cancer. Magnolol (Mag), see structure Fig. S1, is a phenolic polyhydroxy compound isolated from the root and stem bark of Magnolia Officinalis 5. It had been found to inhibit proliferation and induce apoptosis in MCF-7 breast cancer cells via the intrinsic pathway with release of apoptosis inducing factor from mitochondria 5,6. Studies have also shown that Mag inhibited cell growth and HER2-mediated tumor metastasis in human HER2-cancer cells 7. Although, Mag might be considered a potential lead drug in breast cancer treatment yet, its delivery is usually hampered by poor aqueous solubility and low oral bioavailability 6,8. Hence, its incorporation in a smart nanocarrier is expected to improve its delivery characteristics and boost its anticancer properties especially with the incorporation of multifunctional adjuvants.

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“…5b, c). In combination with targeting molecules, LPPC has been shown to be a specific delivery vector for an antitumour drugs to tumour cells [36]. The targeting molecule RBDV-IgG1 Fc (RBDV) further causes specific gene transfection in vitro ( Fig.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that LPPC can be complexed with proteins in a non-covalent linkage manner, and the bound proteins which still retain their biological activity cannot be displaced by unbound proteins [34,35]. With this property, LPPC has been used as a vector for targeted tumour therapy in combination with Herceptin [36]. However, the use of LPPC for targeting gene therapy has been still unknown.…”

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confidence: 99%

Lipoplex-based targeted gene therapy for the suppression of tumours with VEGFR expression by producing anti-angiogenic molecules

Chen

et al. 2020

J Nanobiotechnol

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Background: The anti-angiogenic fusion protein RBDV-IgG1 Fc (RBDV), which comprises the receptor-binding domain of vascular endothelial growth factor-A (VEGF-A), has shown antitumour effects by reducing angiogenesis in vivo. This study used the cationic lipoplex lipo-PEG-PEI-complex (LPPC) to simultaneously encapsulate both the RBDV targeting protein and the RBDV plasmid (pRBDV) without covalent bonds to assess VEGFR targeting gene therapy in mice with melanoma in vivo. Results: LPPC protected the therapeutic transgene from degradation by DNase, and the LPPC/RBDV complexes could specifically target VEGFR-positive B16-F10 cells both in vitro and in vivo. With or without RBDV protein-targeting direction, the pRBDV-expressing RBDV proteins were expressed and reached a maximal concentration on the 7th day in the sera after transfection in vivo and significantly elicited growth suppression against B16-F10 melanoma but not IgG1 control proteins. In particular, LPPC/pRBDV/RBDV treatment with the targeting molecules dramatically inhibited B16-F10 tumour growth in vivo to provide better therapeutic efficacy than the treatments with gene therapy with IgG1 protein targeting or administration of a protein drug with RBDV. Conclusions: The simultaneous combination of the LPPC complex with pRBDV gene therapy and RBDV protein targeting might be a potential tool to conveniently administer targeted gene therapy for cancer therapy.

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Specific drug delivery efficiently induced human breast tumor regression using a lipoplex by non-covalent association with anti-tumor antibodies

Cited by 31 publications

References 26 publications

<p>Encapsulated <em>n</em>-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma</p>

<p>Encapsulated <em>n</em>-Butylidenephthalide Efficiently Crosses the Blood–Brain Barrier and Suppresses Growth of Glioblastoma</p>

Near IR responsive targeted integrated lipid polymer nanoconstruct for enhanced magnolol cytotoxicity in breast cancer

Lipoplex-based targeted gene therapy for the suppression of tumours with VEGFR expression by producing anti-angiogenic molecules

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