Abstract:
:Many cancer therapy regimes still rely heavily on the systemic administration of toxic chemotherapeutic agents. Ultrasound contrast agents consisting of microbubbles (MBs) have emerged as a drug delivery vehicle to overcome the challenges associated with systemic chemotherapy. Here, we describe the development of non-immunogenic, functionalized polylactic acid (PLA) MBs for use in targeted cancer therapy. Our previous studies have shown that the balance between acoustic behavior and improved immune avoidance was scalable and successful to different degrees with two different PEGylation methods and was best achieved using incorporation of PEG-PLA at 5 wt % and for a LipidPEG at 1 wt %. Capitalizing on this, we now attach a targeting ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which selectively induces tumor cell death upon binding to cancer cell-specific surface receptors, initiating a transmembrane apoptosis signal. Additionally, the functionalized MBs were designed to coencapsulate doxorubicin (Dox) that can be released from the polymer shell in response to ultrasound focused at the tumor site, shielding healthy tissues from toxicity while increasing the potency and efficiency of treatment to the tumor tissue. Ligation of TRAIL reduced the encapsulation efficiency for Dox compared to those of their non-ligated counterparts (p < 0.0001) by approximately 34% for 100% PLA, 23% for 5 wt % PEG-PLA, and 30% for the 1 wt % LipidPEG platform. All platforms exhibited a burst effect (<7%, p < 0.0001), and sustained release lasted for over 150 h. This work has resulted in a choice of effective ultrasound-triggered, non-immunogenic, targeted drug delivery agents for potential use in cancer therapy. These platforms have many advantages over the systemic administration of chemotherapeutic drugs and represent a promising treatment to better serve the population with solid cancerous tumors as a whole.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Jablonowski LJ,Teraphongphom NT,Wheatley MAdoi
10.1021/acs.molpharmaceut.7b00451subject
Has Abstractpub_date
2017-10-02 00:00:00pages
3448-3456issue
10eissn
1543-8384issn
1543-8392journal_volume
14pub_type
杂志文章abstract::Combinatorial chemistry has enabled the production of very potent drugs that might otherwise suffer from poor solubility and low oral bioavailability. One approach to increase solubility is to make the drug amorphous, which leads to problems associated with drug stability. To improve stability, one option is to molecu...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400712m
更新日期:2014-07-07 00:00:00
abstract::Photodynamic therapy (PDT) is a light-induced chemical reaction that produces localized tissue damage for the treatment of cancers and other nonmalignant conditions. The activation of photosensitizers in a target tissue is accomplished with a specific light source in the presence of molecular oxygen. In the clinic, pa...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100060v
更新日期:2010-08-02 00:00:00
abstract::Tablets which were binary mixtures of pioglitazone hydrochloride (PioHCl) with magnesium stearate (MgSt), croscarmellose sodium (CCS), microcrystalline cellulose, or lactose monohydrate were prepared. Two sets of experiments, using intact tablets, were performed. (i) Tablets containing PioHCl (90% w/w) and MgSt were e...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b01052
更新日期:2017-04-03 00:00:00
abstract::Plant or microbial lectins are known to exhibit potent antiviral activities against viruses with glycosylated surface proteins, yet the mechanism(s) by which these carbohydrate-binding proteins exert their antiviral activities is not fully understood. Hepatitis C virus (HCV) is known to possess glycosylated envelope p...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400399b
更新日期:2013-12-02 00:00:00
abstract::Current cancer chemotherapies commonly suffer from nonspecificity, drug resistance, poor bioavailability, and narrow therapeutic indices. To achieve the optimum drug efficacy, we designed a polymeric drug delivery system for targeted intracellular delivery of a clinically approved, water-soluble anticancer drug, gemci...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00935
更新日期:2016-05-02 00:00:00
abstract::Safe and effective gene delivery is essential to the success of gene therapy. We synthesized and characterized a novel nonviral gene delivery system in which folate (FA) molecules were functioned as blockers on cationic polyrotaxanes (PR) composed of poly(ethylenimine) (PEI)(600)-grafted α-cyclodextrin rings linearize...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200315c
更新日期:2012-05-07 00:00:00
abstract::The objectives of this study were as follows: (i) To develop an in silico technique, based on molecular dynamics (MD) simulations, to predict glass transition temperatures (Tg) of amorphous pharmaceuticals. (ii) To computationally study the effect of plasticizer on Tg. (iii) To investigate the intermolecular interacti...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400118v
更新日期:2013-11-04 00:00:00
abstract::Ipratropium bromide, an anticholinergic drug used for the treatment of asthma and chronic obstructive pulmonary disease, has low oral bioavailability, but systemic exposure, superior to oral administration, can be achieved by inhalation. Therefore, we investigated the pulmonary absorption mechanism of ipratropium usin...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp900206j
更新日期:2010-02-01 00:00:00
abstract::Reversible aqueous lipidization (REAL) at the interdisulfide bond has been shown to improve the deliverability of some peptide drugs. Recently, we developed a nonreversible aqueous lipidization method targeted at the interdisulfide bond of salmon calcitonin (sCT). The resultant derivative had comparable hypocalcemic a...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp8000167
更新日期:2008-07-01 00:00:00
abstract::The objective of this study was to enhance oral mucosal permeation of fenretinide by coincorporation of propylene glycol (PG) and menthol in fenretinide/Eudragit RL PO mucoadhesive patches. Fenretinide is an extremely hydrophobic chemopreventive compound with poor tissue permeability. Coincorporation of 5-10 wt % PG (...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200655k
更新日期:2012-04-02 00:00:00
abstract::The barrier epithelia of the cornea and retina control drug and nutrient access to various compartments of the human eye. While ocular transporters are likely to play a critical role in homeostasis and drug delivery, little is known about their expression, localization and function. In this study, the mRNA expression ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300429e
更新日期:2013-02-04 00:00:00
abstract::Amorphous solids and crystalline salts are both of interest as a means of improving the dissolution characteristics and apparent solubility of poorly water soluble active pharmaceutical ingredients which have low bioavailability in humans. The theory and selection of both crystalline drug substance salt forms and amor...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp8000342
更新日期:2008-11-01 00:00:00
abstract::For aggressive brain glioblastoma, the therapy is significantly impaired by blood-brain barrier (BBB) and blood-tumor barrier (BTB). Choosing more than one target from the pool of tumor-stroma interactions is profoundly beneficial to therapeutic approaches. Thus, a multifunctional liposomal system based on anchoring t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00819
更新日期:2017-04-03 00:00:00
abstract::Platinum(IV) complexes generally require reduction to reactive Pt(II) species to exert their chemotherapeutic activity. The process of reductive activation of (15)N-labeled (OC-6-43)-bis(acetato)diamminedichloridoplatinum(IV), in the presence of nicotinamide adenine dinucleotide (NADH) and horse heart cytochrome c (cy...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00438
更新日期:2016-09-06 00:00:00
abstract::Milk has been used as a vehicle for the delivery of antimalarial drugs during clinical trials to test for a food effect and artefenomel (OZ439) showed enhanced oral bioavailability with milk. However, the nature of the interaction between milk and OZ439 in the gastrointestinal tract remains poorly understood. To under...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00541
更新日期:2018-08-06 00:00:00
abstract::Two-phase gas-liquid microfluidic reactors provide shear processing control of SN-38-loaded polymer nanoparticles (SN-38-PNPs). We prepare SN-38-PNPs from the block copolymer poly(methyl caprolactone- co-caprolactone)- block-poly(ethylene oxides) (P(MCL- co-CL)- b-PEO) using bulk and microfluidic methods and at differ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00874
更新日期:2019-01-07 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 this article, thermal properties, molecular dynamics, crystallization kinetics, and intermolecular interactions in pure naproxen (NAP), its amide (NH2-NAP), and four esters (methyl, Met-NAP; isopropyl, Iso-NAP; hexyl, Hex-NAP; and benzyl, Ben-NAP) have been investigated using differential scanning calorimetry as we...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00725
更新日期:2018-10-01 00:00:00
abstract::The particular characteristics of the tumor microenvironment have the potential to strongly promote tumor growth, metastasis and angiogenesis and induce drug resistance. Therefore, the development of effective, systemic therapeutic approaches specifically based on the tumor microenvironment is highly desirable. Hypoxi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300193f
更新日期:2012-10-01 00:00:00
abstract::Whether luteolin inhibits HBV replication has not been validated and the underlying mechanism of which has never been elucidated. In this study, we show that luteolin reduces HBV DNA replication in HepG2.2.15 cells. Luteolin effectively inhibited the expression of hepatocyte nuclear factor 4α (HNF4α) and its binding t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00789
更新日期:2016-02-01 00:00:00
abstract::The objective was to determine the disposition of polymer nanoparticles and an associated, lipophilic, model "active" component on and within the skin following topical application. Polystyrene and poly(methyl methacrylate) nanoparticles containing covalently bound fluorescein methacrylate and dispersed Nile Red were ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp9001188
更新日期:2009-09-01 00:00:00
abstract::A highly versatile and step-economical route to a new class of guanidinium-rich molecular transporters and evaluation of their ability to complex, deliver, and release siRNA are described. These new drug/probe delivery systems are prepared in only two steps, irrespective of length or composition, using an organocataly...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500581r
更新日期:2015-03-02 00:00:00
abstract::Tumor endothelial marker 8 (TEM8) is a cell surface receptor that is highly expressed in a variety of human tumors and promotes tumor angiogenesis and cell growth. Antibodies targeting TEM8 block tumor angiogenesis in a manner distinct from the VEGF receptor pathway. Development of a TEM8 imaging agent could aid in pa...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500056d
更新日期:2014-11-03 00:00:00
abstract::The adenovirus (Ad) is widely used as a vaccine because of its ability to induce a cellular and humoral immune response. In addition, human clinical trials have validated the safety and efficacy of Ad as a vaccine vector. The traditional approach for employing the adenovirus as vaccine is to configure the antigen gene...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/acs.molpharmaceut.8b00591
更新日期:2018-12-03 00:00:00
abstract::Positron emission tomography (PET) imaging using 68Ga-labeled bisphosphonates to target bone metastasis could be a valuable tool in cancer diagnosis and monitoring therapeutic treatment. A 68Ga labeled ligand, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC) containing one bisphos...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00103
更新日期:2020-05-04 00:00:00
abstract::Effective penetration of drug-carrying nanoparticles into solid tumors is a major challenge in cancer therapy. Exploration of the physicochemical properties of nanoparticles that affect penetration efficiency is required to achieve maximum therapeutic effects. Here, we used confocal laser scanning microscopy to evalua...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00051
更新日期:2017-06-05 00:00:00
abstract::Lung-delivered polymer nanoparticles provoked dysfunction of the essential lung surfactant system. A steric shielding of the nanoparticle surface with poloxamers could minimize the unwanted interference of polymer nanoparticles with the biophysical function of lung surfactant. The extent of poly(styrene) and poly(lact...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00477
更新日期:2017-10-02 00:00:00
abstract::Organic anion transporting polypeptides 1B1 and 1B3 are transporters selectively expressed on the basolateral membrane of the hepatocyte. Several studies reveal that they are involved in drug-drug interactions, cancer, and hyperbilirubinemia. In this study, we developed a set of classification models for OATP1B1 and 1...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00583
更新日期:2015-12-07 00:00:00
abstract::sec-Butylpropylacetamide (SPD) is the amide derivative of valproic acid (VPA). SPD possess a wide-spectrum anticonvulsant profile better than that of VPA and blocks status epilepticus (SE) induced by pilocarpine and organophosphates. The activity of SPD on SE is better than that of benzodiazepines (BZDs) in terms of t...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00221
更新日期:2016-07-05 00:00:00
abstract::Metastatic breast cancer is incurable. The goal of this study was to develop a positron emission tomography (PET)/near-infrared fluorescent (NIRF) probe for imaging CD105 expression in breast cancer experimental lung metastasis. TRC105, a chimeric anti-CD105 antibody, was dual-labeled with a NIRF dye (IRDye 800CW) and...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300277f
更新日期:2012-08-06 00:00:00