Abstract:
:Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, these studies developed and characterized a library of dextrin-colistin conjugates (dextrin molecular weight: 7500-48,000 g/mol) as a means of targeting the delivery of colistin. Optimum colistin release kinetics (following dextrin degradation by physiological concentrations of amylase (100 IU/L)) were observed in conjugates containing low molecular weight (∼7500 g/mol) dextrin with ∼1 mol % succinoylation (∼80% drug release within 48 h, compared to ∼33% from sodium colistin methanesulfonate (CMS, Colomycin)). These conjugates exhibited comparable antimicrobial activity to CMS in conventional MIC assays against a range of Gram-negative pathogens, but with significantly reduced in vitro toxicity toward kidney (IC₅₀ = CMS, 15.4 μg/mL; dextrin-colistin, 63.9 μg/mL) and macrophage (IC₅₀ = CMS, 111.3 μg/mL; dextrin-colistin, 303.9 μg/mL) cells. In vivo dose-escalation studies in rats demonstrated improved pharmacokinetics of the conjugates, with prolonged plasma levels of colistin (t₁/₂ 135-1271 min vs 53 min) and decreased toxicity, compared to colistin sulfate. These studies highlight the potential utility of "nanoantibiotic" polymer therapeutics to aid the safe, effective, and targeted delivery of colistin in the management of MDR infections.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Ferguson EL,Azzopardi E,Roberts JL,Walsh TR,Thomas DWdoi
10.1021/mp500584usubject
Has Abstractpub_date
2014-12-01 00:00:00pages
4437-47issue
12eissn
1543-8384issn
1543-8392journal_volume
11pub_type
杂志文章abstract::Understanding protein stability is central to combatting protein aggregation diseases and developing new protein therapeutics. At the high concentrations often present in biological systems, purified proteins can exhibit undesirable high solution viscosities and poor solubilities mediated by short-range electrostatic ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00322
更新日期:2017-10-02 00:00:00
abstract::TGX-221 is a highly potent phosphoinositide 3-kinase β (PI3Kβ) inhibitor that holds great promise as a novel chemotherapeutic agent to treat prostate cancer. However, poor solubility and lack of targetability limit its therapeutic applications. The objective of this present study is to develop a peptide-drug conjugate...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200007b
更新日期:2011-06-06 00:00:00
abstract::Due to overexpression of glycyrrhetinic acid (GA) receptor in liver cancer cells, glycyrrhetinic acid modified recombinant human serum albumin (rHSA) nanoparticles for targeting liver tumor cells may result in increased therapeutic efficacy and decreased adverse effects of cancer therapy. In this study, doxorubicin (D...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp500394v
更新日期:2015-03-02 00:00:00
abstract::We investigated the effect of polymer composition on nifedipine (NIF) dissolution through molecular-level characterization of NIF/hypromellose (HPMC)/Eudragit S (EUD-S) ternary solid dispersions. The dissolution rates and molecular states of NIF and polymers were evaluated in NIF/HPMC/EUD-S spray-dried samples (SPDs) ...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b00523
更新日期:2018-09-04 00:00:00
abstract::The effect of a lipidated prodrug of mitomycin C (MLP) on the membrane of a pegylated liposome formulation (PL-MLP), also known as Promitil, was characterized through high-sensitivity differential scanning calorimetry (DSC) and cryo-TEM. The thermodynamic analysis demonstrated that MLP led to the formation of heteroge...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00865
更新日期:2017-12-04 00:00:00
abstract::This work demonstrates the way to achieve efficient and target specific delivery of a graphene quantum dot (GQD) using hyaluronic acid (HA) (GQD-HA) as a targeting agent. HA has been anchored to a GQD that accepts the fascinating adhesive properties of the catechol moiety, dopamine hydrochloride, conjugated to HA, whi...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400219u
更新日期:2013-10-07 00:00:00
abstract::As microRNAs (miRNAs) have been reported to be a type of novel high-value small molecule (SM) drug targets for disease treatments, many researchers are engaged in the field of exploring new SM-miRNA associations. Nevertheless, because of the high cost, adopting traditional biological experiments constrains the efficie...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00384
更新日期:2019-07-01 00:00:00
abstract::It is a challenge to formulate polymer based nanoparticles of therapeutic proteins as excipients and process conditions affect stability and structural integrity of the protein. Hence, understanding the protein stability and complex aggregation phenomena is an important area of research in therapeutic protein delivery...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5003653
更新日期:2015-04-06 00:00:00
abstract::Solubility limited compounds require enabling formulations such as amorphous solid dispersions (ASDs) to increase the apparent solubility by dissolving to a concentration higher than the equilibrium solubility of the drug. This may lead to subsequent precipitation and thus the loss of the solubility advantage. Althoug...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00788
更新日期:2017-01-03 00:00:00
abstract::The controlled release of anticancer drugs at the tumor site is a central challenge in treating cancer. To achieve this goal, our strategy was based on tumor-specific targeting and ultrasound-triggered release of an anticancer agent from liposomal nanocarriers. To enhance the ultrasound-triggered drug release, we inco...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b00194
更新日期:2019-07-01 00:00:00
abstract::Dendrimers are being explored in many preclinical studies as drug, gene, and imaging agent delivery systems. Understanding their detailed organ, tissue, cellular uptake, and retention can provide valuable insights into their effectiveness as delivery vehicles and the associated toxicity. This work explores a fluoresce...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp400371r
更新日期:2013-12-02 00:00:00
abstract::Viral nanotechnology is an emerging and highly interdisciplinary field in which viral nanoparticles (VNPs) are applied in diverse areas such as electronics, energy and next-generation medical devices. VNPs have been developed as candidates for novel materials, and are often described as "programmable" because they can...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp100225y
更新日期:2011-02-07 00:00:00
abstract::The 1:1 cocrystal of the antifungal agent ketoconazole with p-aminobenzoic acid was successfully crystallized and systematically characterized by a physical and pharmacological point of view. Crystal structure determination confirmed the cocrystal identity, giving full insight in its crystal packing and degree of diso...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b01178
更新日期:2020-03-02 00:00:00
abstract::We investigated the phase separation behavior and maintenance mechanism of the supersaturated state of poorly water-soluble nifedipine (NIF) in hypromellose (HPMC) derivative solutions. Highly supersaturated NIF formed NIF-rich nanodroplets through phase separation from aqueous solution containing HPMC derivative. Dis...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00178
更新日期:2017-07-03 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...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00346
更新日期:2017-09-05 00:00:00
abstract::Contrast-enhanced ultrasound imaging has shown promise in the field of molecular imaging. This technique relies upon the adhesion of ultrasound contrast agent (UCA) to targeted molecular markers of disease. This is accomplished by coating the surface of the contrast agent with a ligand that specifically binds to the i...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp0600541
更新日期:2006-09-01 00:00:00
abstract::Retinal pigment epithelium, which forms the outer blood-retinal barrier, is a critical barrier for transport of drugs to the retina. The purpose of this study was to develop a pigmented MDCK (P-MDCK) cell line as a rapidly established in vitro model for the outer blood-retinal barrier to assess the influence of melani...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300305f
更新日期:2012-11-05 00:00:00
abstract::The present work reports a thorough conformational analysis of iodinated contrast media: iomeprol, iopamidol (the world's most utilized contrast agent), and iopromide. Its main aim is the understanding of the complex structural features of these atropisomeric molecules, characterized by the presence of many conformers...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp5007486
更新日期:2015-06-01 00:00:00
abstract::Erythropoietin (EPO), a hematopoietic growth factor and a promising therapy for Alzheimer's disease, has low permeability across the blood-brain barrier. The transferrin receptor antibody fused to EPO (TfRMAb-EPO) is a chimeric monoclonal antibody that ferries EPO into the brain via the transvascular route. However, T...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.0c00231
更新日期:2020-08-03 00:00:00
abstract::Compared with peripheral tumors, glioma is very difficult to treat, not only because it has general features of tumor but also because the therapy has been restricted by the brain-blood barrier (BBB). The two main features of tumor growth are angiogenesis and proliferation of tumor cells. RNA interference (RNAi) can d...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.6b00051
更新日期:2016-05-02 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
pub_type: 杂志文章
doi:10.1021/mp300712a
更新日期:2013-06-03 00:00:00
abstract::Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulatio...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.9b01004
更新日期:2020-01-06 00:00:00
abstract::Most anticancer drugs are poorly soluble and nonspecific, which restricts their clinical application. Drug conjugates, as a prodrug strategy, provide the possibility to overcome these shortcomings, especially combined with nanotechnology. Drug conjugate nanoparticles possess the advantages of high drug loading capacit...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.5b00631
更新日期:2016-01-04 00:00:00
abstract::Tumor-associated inflammation has been linked to angiogenesis, metastasis and poor prognosis. The 18 kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor (PBR), is expressed in activated immune cells such as macrophages, but also in a number of cancer cell lines such as those of breast...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp100433c
更新日期:2011-06-06 00:00:00
abstract::Recent developments in pharmaceutical technology have facilitated the design and production of modified release formulas for drugs whose physical, chemical or biological properties impede release and thus might compromise their efficacy or safety. One such drug is morphine, whose short half-life requires repeated dose...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp200019q
更新日期:2011-04-04 00:00:00
abstract::Ratiometric fluorescence and cellular fractionation studies were employed to characterize the intracellular trafficking dynamics of antibody-poly(propylacrylic acid) (PPAA) conjugates in CD22+ RAMOS-AW cells. The HD39 monoclonal antibody (mAb) directs CD22-dependent, receptor-mediated uptake in human B-cell lymphoma c...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp300338s
更新日期:2012-12-03 00:00:00
abstract::Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-43...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.7b00793
更新日期:2018-03-05 00:00:00
abstract::Liposomes are widely used for systemic delivery of chemotherapeutic agents to reduce their nonspecific side effects. Gemcitabine (Gem) makes a great candidate for liposomal encapsulation due to the short half-life and nonspecific side effects; however, it has been difficult to achieve liposomal Gem with high drug load...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/acs.molpharmaceut.8b01284
更新日期:2019-07-01 00:00:00
abstract::The transfer of genetic material into cells using nonviral vectors offers unique potential for therapeutics; however, the efficacy of delivery depends upon a poorly understood, multistep pathway, limiting the prospects for successful gene delivery. Mechanistic insight into DNA association and release has been hampered...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章
doi:10.1021/mp3002864
更新日期:2012-09-04 00:00:00
abstract::Targeting of drugs administered systemically relies on the higher affinity of ligands for specific receptors to obtain selectivity in drug response. However, achieving the same goal inside the bladder is much easier with an intelligent pharmaceutical approach that restricts drug effects by exploiting the pelvic anatom...
journal_title:Molecular pharmaceutics
pub_type: 杂志文章,评审
doi:10.1021/mp060001j
更新日期:2006-07-01 00:00:00