Abstract:
:We developed a modular multifunctional nonviral gene delivery system by targeting the overexpressed cancer surface receptor α5β1 integrin and the upregulated transcriptional activity of the cancer resistance mediating transcription factor NF-κB, thereby introducing a new form of transcriptional targeting. NF-κB regulated therapy can improve specificity of gene expression in cancer tissue and also may offset NF-κB mediated cancer resistance. We delivered a luciferase gene under the control of an NF-κB responsive element (pNF-κB-Luc) encapsulated in a PR_b peptide functionalized stealth liposome that specifically targets the α5β1 integrin and achieved increased gene expression in DLD-1 colorectal cancer cells compared to BJ-fibroblast healthy cells in vitro. The multitargeted system was also able to differentiate between cancer cells and healthy cells better than either of the individually targeted systems. In addition, we constructed a novel cancer therapeutic plasmid by cloning a highly potent diphtheria toxin fragment A (DTA) expressing gene under the control of an NF-κB responsive element (pNF-κB-DTA). A dose-dependent reduction of cellular protein expression and increased cytotoxicity in cancer cells was seen when transfected with PR_b functionalized stealth liposomes encapsulating the condensed pNF-κB-DTA plasmid. Our therapeutic delivery system specifically eradicated close to 70% of a variety of cancer cells while minimally affecting healthy cells in vitro. Furthermore, the modular nature of the nonviral design allows targeting novel pairs of extracellular receptors and upregulated transcription factors for applications beyond cancer gene therapy.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Adil MM,Levine RM,Kokkoli Edoi
10.1021/mp400535vsubject
Has Abstractpub_date
2014-03-03 00:00:00pages
849-58issue
3eissn
1543-8384issn
1543-8392journal_volume
11pub_type
杂志文章abstract::Recent studies on aqueous supersaturated lipophilic drug solutions prepared by methods including antisolvent addition, pH swing, or dissolution of amorphous solid dispersions (ASDs) have demonstrated that when crystallization is slow, these systems undergo liquid-liquid phase separation (LLPS) when the concentration o...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00202
更新日期:2016-06-06 00:00:00
abstract::The need for an efficacious and safe oral anticoagulant that does not require monitoring has been largely unmet. Many efforts have centered on preparing orally available heparin to improve patient compliance. In this study, novel orally active heparin derivatives (LHD), i.e. low molecular weight heparin (LMWH) conjuga...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900319k
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abstract::Lung cancer is a kind of malignant tumor with high morbidity and metastasis tendency. Gambogic acid (GA) has demonstrated significant antitumor activity in vitro, but its poor water-solubility and adverse effects restrict its application in vivo and in clinic. In this study, a passive-targeting GA delivery system was ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00161
更新日期:2018-05-07 00:00:00
abstract::P-glycoprotein (Pgp) is highly expressed on blood-brain barrier (BBB) and glioblastoma (GB) cells, particularly on cancer stem cells (SC). Pgp recognizes a broad spectrum of substrates, limiting the therapeutic efficacy of several chemotherapeutic drugs in eradicating GB SC. Finding effective and safe inhibitors of Pg...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00018
更新日期:2019-08-05 00:00:00
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journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00898
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abstract::Delivery of antigenic protein to the cytosol of antigen-presenting cells (APCs), such as macrophages (MPhi) and dendritic cells (DCs), is required for an efficient CD8 T-cell-mediated immune response. We have previously shown that co-encapsulation of antigenic protein inside pH-sensitive liposomes with listeriolysin O...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp049896v
更新日期:2005-01-01 00:00:00
abstract::Deep generative adversarial networks (GANs) are the emerging technology in drug discovery and biomarker development. In our recent work, we demonstrated a proof-of-concept of implementing deep generative adversarial autoencoder (AAE) to identify new molecular fingerprints with predefined anticancer properties. Another...
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pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00346
更新日期:2017-09-05 00:00:00
abstract::In vivo peptide inhibition of tumor suppressor p53 binding to the protein MDM2 is hampered by inefficient delivery of the peptide. Our approach to couple a hydrophobic lipid-like tail on the inhibitory peptide p53(14-29) allowed its intracellular delivery in vitro, in a panel of different cell lines. The constructed c...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100193h
更新日期:2010-12-06 00:00:00
abstract::Despite significant potential of oligonucleotides (ONs) for therapeutic and diagnostic applications, rapid and widespread intracellular delivery of ONs in cells situated in tissues such as skin, head and neck cavity, and eye has not been achieved. This study was aimed at evaluating the synergistic combination of micro...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300717f
更新日期:2013-08-05 00:00:00
abstract::Harmane and norharmane are representative members of the large group of natural β-carboline alkaloids featured with diverse pharmacological activities. In blood, these agents are transported by human serum albumin (HSA) which has a profound impact on the pharmacokinetic and pharmacodynamic properties of many therapeut...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400531n
更新日期:2013-12-02 00:00:00
abstract::Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs posse...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00670
更新日期:2016-04-04 00:00:00
abstract::The molecular mechanisms of autophagy in polyethylenimine (PEI)-treated cells are not well understood because of the use of nonspecific autophagy inhibitors. Here, we applied autophagy-related gene expression analysis to pinpoint the molecular mechanisms of autophagy in PEI-treated wild-type and atg5 gene knockout (at...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500111u
更新日期:2014-09-02 00:00:00
abstract::The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has receiv...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300502m
更新日期:2013-05-06 00:00:00
abstract::The systemic pharmacokinetics and pharmacodynamics of small molecules are determined by subcellular transport phenomena. Although approaches used to study the subcellular distribution of small molecules have gradually evolved over the past several decades, experimental analysis and prediction of cellular pharmacokinet...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp200092v
更新日期:2011-10-03 00:00:00
abstract::Polymeric micelles are emerging as a highly integrated nanoplatform for cancer targeting, drug delivery and tumor imaging applications. In this study, we describe a multifunctional micelle (MFM) system that is encoded with a lung cancer-targeting peptide (LCP), and encapsulated with superparamagnetic iron oxide (SPIO)...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp9001393
更新日期:2010-02-01 00:00:00
abstract::p53 is a key tumor suppressor gene involved in key cellular processes and implicated in cancer therapy. However, it is inactivated in more than 50% of all cancers due to mutation or overexpression of its negative regulators. This leads to drug resistance and poor chemotherapeutic outcome as most clinical drugs act via...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00348
更新日期:2016-07-05 00:00:00
abstract::Penetratin is a classical cell-penetrating peptide with the potential to assist in the transmembrane delivery of proteins or drugs. However, the synthesis and application of cholesterol-penetratin (Chol-P) conjugates as nonviral delivery systems for microRNAs or drugs have not previously been reported. In this study, ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00211
更新日期:2016-07-05 00:00:00
abstract::"Nano" drug delivery carriers are established technologies for improving the therapeutic index of chemotherapeutic drugs and overcoming formulation challenges of poorly water-soluble compounds. Two important remaining challenges, however, are the need to formulate drugs on a case-by-case basis (due to the specific che...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp5001247
更新日期:2014-06-02 00:00:00
abstract::Drug self-delivery systems consisting of small-molecule active drugs with nanoscale features for intracellular delivery without the need for additional polymeric carriers have drawn much attention recently. In this work, we proposed a highly efficient strategy to fabricate protonized and reduction-responsive self-asse...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00349
更新日期:2019-09-03 00:00:00
abstract::Doxorubicin (DOX) is one of the most commonly used antineoplastic agents, but its clinical application is oftentimes coupled with severe side effects. Selective delivery of DOX to tumors via nanosized drug carrier represents an attractive approach to this problem. Previously, we developed a dual functional nanomicella...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500389v
更新日期:2014-11-03 00:00:00
abstract::One hypothesis for persisting HIV-associated neurocognitive disorders (HAND) in effectively treated individuals is the limited permeation of antiretroviral agents (ARV) across the blood-brain barrier (BBB). However, the physicochemical factors limiting the brain entry of a given ARV and the mutual interactions of comb...
journal_title:Molecular pharmaceutics
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doi:10.1021/mp300712a
更新日期:2013-06-03 00:00:00
abstract::Superoxide dismutase 1 (SOD1) efficiently catalyzes dismutation of superoxide, but its poor delivery to the target sites in the body, such as brain, hinders its use as a therapeutic agent for superoxide-associated disorders. Here to enhance the delivery of SOD1 across the blood-brain barrier (BBB) and in neurons the e...
journal_title:Molecular pharmaceutics
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doi:10.1021/mp300496x
更新日期:2013-01-07 00:00:00
abstract::Amphotericin B is a lifesaving polyene antibiotic used in the treatment of systemic mycoses. Unfortunately, the pharmacological applicability of this drug is limited because of its severe toxic side effects. At the same time, the lack of a well-defined mechanism of selectivity hampers the efforts to rationally design ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00572
更新日期:2018-09-04 00:00:00
abstract::An effective short interfering RNA (siRNA) delivery system protects the siRNA from degradation, facilitates its cellular uptake, and promotes its release into the cytoplasm. Local administration of siRNA presents advantages over systemic administration, such as the possibility to use lower doses and allow local and su...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01141
更新日期:2017-05-01 00:00:00
abstract::meta-Tetra(hydroxyphenyl)chlorin (mTHPC) is one of the most potent second-generation photosensitizers, clinically used for photodynamic therapy (PDT) of head and neck squamous cell carcinomas. However, improvements are still required concerning its present formulation (i.e., Foscan, a solution of mTHPC in ethanol/prop...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b01280
更新日期:2020-04-06 00:00:00
abstract::Topical delivery of small interfering RNA (siRNA) can be an attractive method for the treatment of skin diseases and improving the quality of life of patients. However, it is difficult for siRNA to pass through the two major barriers of the skin: the stratum corneum (SC) and tight junctions. We have previously reporte...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00997
更新日期:2021-01-04 00:00:00
abstract::The bicarbonate buffer capacity is usually considered in a phase-homogeneous system, at equilibrium, with no CO2 transfer between the liquid buffer phase and another phase. However, typically, an in vitro bicarbonate buffer-based system is a phase-heterogeneous system, as it entails continuously sparging (bubbling) th...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00783
更新日期:2018-11-05 00:00:00
abstract::In previous studies, we developed a new technique (ionic gelation vibrational jet flow; IGVJF) in order to encapsulate pancreatic β-cells, for insulin in vivo delivery, and diabetes treatment. The fabricated microcapsules showed good morphology but limited cell functions. Thus, this study aimed to optimize the IGVJF t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00220
更新日期:2017-08-07 00:00:00
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journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00582
更新日期:2015-12-07 00:00:00
abstract::The wet form of age-related macular degeneration (AMD) is a leading cause of blindness among elderly Americans and is characterized by abnormal vessel growth, termed choroidal neovascularization (CNV). Integrin α5β1 is a transmembrane receptor that binds matrix macromolecules and proteinases to stimulate angiogenesis....
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00056
更新日期:2016-09-06 00:00:00