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ATTEMPTS System: A Macromolecular Prodrug Strategy for Cancer Drug Delivery.
Huang, Yongzhuo,Park, Yoon Shin,Wang, Jianxin,Moon, Cheol,Kwon, Young Min,Chung, Hee Sun,Park, Yoon Jeong,Yang, Victor C Bentham Science Publishers 2010 CURRENT PHARMACEUTICAL DESIGN Vol.16 No.21
<P>In order to reduce systemic toxicity and effectively deliver macromolecular drug into tumor cells, a system termed 'ATTEMPTS' (antibody targeted, [protamine] triggered, electrically modified prodrug-type strategy) was developed in our laboratory. This approach was adapted from our previously reported heparin/protamine-based system for controlled delivery of protease drugs such as tissue- specific plasminogen activator (tPA). In this 'ATTEMPTS' system, the cell-permeable protein drugs are synthesized by conjugating proteins to cell-penetrating peptides (CPPs). Cell penetration ability of such CPP-protein conjugates would initially be disabled, acting as a 'prodrug', by forming polyelectrolyte complexes with a functionalized heparin-antibody moiety. The complexes would accumulate in tumor sites by the antibody targeting function, and then the local release of CPP-protein conjugates would be triggered by protamine. We applied this system to the macromolecular anticancer agents, such as the protein drugs (gelonin and asparaginase) as well as the polymerdrugs (polyrotaxane-doxorubicin and polyrotaxane-camptothecin). Both in vitro and preliminary in vivo studies demonstrated the regulable cell penetration behavior based on the competitive ionic interactions between CPP/heparin and heparin/protamine. Thus, this ATTEMPTS approach provides a multi-functionalized system incorporating the features of targeting, prodrug-like, triggerable release, and cell penetration ability for the delivery of macromolecular anticancer agents. A summary of our work on 'ATTEMPTS' is presented in this review.</P>
Park, Yoon Shin,Huang, Yongzhuo,Park, Yoon Jeong,David, Allan E.,White, Lindsay,He, Huining,Chung, Hee Sun,Yang, Victor C. Elsevier 2010 Journal of controlled release Vol.144 No.1
<P><B>Abstract</B></P><P>Hypoxia is a strong modulator of angiogenesis, accelerating adipose tissue expansion, suggesting that hypoxia inducible factor 1α (HIF1α) can be a novel target for anti-obesity. We conjugated antisense-HIF1α-oligonucleotide (ASO) with low molecular weight protamine (LMWP), a cell-penetrating peptide, to enhance its ability to block hypoxic-angiogenesis, thereby eliciting an anti-obesity effect. Nano-sized ASO-LMWP (AS-L) conjugates enhanced cellular uptake of ASO without yielding a cytotoxic effect and protected the ASO against enzymatic attack and chemical reduction. AS-L showed enhanced intra-cellular localization compared to naked ASO and the complex of ASO with lipofectamine during hypoxic-differentiation. Consequently AS-L induced significant down-regulation of leptin and VEGF gene expressions, thereby reducing fat accumulation in the cell.</P><P>This proof-of-concept study shows that AS-L produces an inhibitory effect on adipogenesis and angiogenesis during differentiation, indicating LMWP mediated ASO delivery can potentially be a safe and promising treatment for obesity.</P> <P><B>Graphical abstract</B></P><P></P>
Shin, Meong Cheol,Min, Kyoung Ah,Cheong, Heesun,Moon, Cheol,Huang, Yongzhuo,He, Huining,Yang, Victor C. Elsevier/North Holland 2017 International journal of pharmaceutics Vol.524 No.1
<P><B>Abstract</B></P> <P>Despite significant progress in prostate cancer treatment, yet, it remains the leading diagnosed cancer and is responsible for high incidence of cancer related deaths in the U.S. Because of the insufficient efficacy of small molecule anti-cancer drugs, significant interest has been drawn to more potent macromolecular agents such as gelonin, a plant-derived ribosome inactivating protein (RIP) that efficiently inhibits protein translation. However, in spite of the great potency to kill tumor cells, gelonin lacks ability to internalize tumor cells and furthermore, cannot distinguish between tumor and normal cells. To address this challenge, we genetically engineered gelonin fusion proteins with varied numbers of F3 peptide possessing homing ability to various cancer cells and angiogenic blood vessels. The <I>E. coli</I> produced F3-gelonin fusion proteins possessed equipotent activity to inhibit protein translation in cell-free protein translation systems to unmodified gelonin; however, they displayed higher cell uptake that led to significantly augmented cytotoxicity. Compared with gelonin fusion with one F3 peptide (F3-Gel), tandem-multimeric F3-gelonins showed even greater cell internalization and tumor cell killing ability. Moreover, when tested against LNCaP <I>s.c.</I> xenograft tumor bearing mice, more significant tumor growth inhibition was observed from the mice treated with tandem-multimeric F3-gelonins. Overall, this research demonstrated the potential of utilizing tandem multimeric F3-modified gelonin as highly effective anticancer agents to overcome the limitations of current chemotherapeutic drugs.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Lu Yan,Huiyuan Wang,Yifan Jiang,Jinhua Liu,Zhao Wang,Yongxin Yang,Shengwu Huang,Yongzhuo Huang 한국고분자학회 2013 Macromolecular Research Vol.21 No.4
Macromolecular drugs become an essential part in neuroprotective treatment. However, the nature of ineffective delivery crossing the blood brain barrier (BBB) renders those macromolecules undruggable for clinical practice. Recently, brain target via intranasal delivery have provided a promising solution to circumventing the BBB. Despite the direct route from nose to brain (i.e. olfactory pathway), there still are big challenges for large compounds like proteins to overcome the multiple delivery barriers such as nasal mucosa penetration, intracellular transport along the olfactory neuron, and diffusion across the heterogeneous brain compartments. Herein presented is an intranasal strategy mediated by cell-penetrating peptide modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles for the delivery of insulin to the brain, a potent therapeutic against Alzheimer’s disease. The results revealed that the cell-penetrating peptide can potentially deliver insulin into brain via the nasal route, showing a total brain delivery efficiency of 6%. It could serve as a potential treatment for neurodegenerative diseases.