Abstract:
:Despite being a major breakthrough in multiple myeloma therapy, carfilzomib (CFZ, a second-generation proteasome inhibitor drug) has been largely ineffective against solid cancer, possibly due to its pharmacokinetic drawbacks including metabolic instability. Recently, quinic acid (QA, a low-affinity ligand of selectins upregulated in peritumoral vasculature) was successfully utilized as a surface modifier for nanoparticles containing paclitaxel. Here, we designed QA-conjugated nanoparticles containing CFZ (CFZ@QANP; the surface of poly(lactic-co-glycolic acid) nanoparticles modified by conjugation with a QA derivative). Compared to the clinically used cyclodextrin-based formulation (CFZ-CD), CFZ@QANP enhanced the metabolic stability and in vivo exposure of CFZ in mice. CFZ@QANP, however, showed little improvement in suppressing tumor growth over CFZ-CD against the murine 4T1 orthotopic breast cancer model. CFZ@QANP yielded no enhancement in proteasomal inhibition in excised tumors despite having a higher level of remaining CFZ than CFZ-CD. These results likely arise from delayed, incomplete CFZ release from CFZ@QANP as observed using biorelevant media in vitro. These results suggest that the applicability of QANP may not be predicted by physicochemical parameters commonly used for formulation design. Our current results highlight the importance of considering drug release kinetics in designing effective CFZ formulations for solid cancer therapy.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Jun Y,Xu J,Kim H,Park JE,Jeong YS,Min JS,Yoon N,Choi JY,Yoo J,Bae SK,Chung SJ,Yeo Y,Lee Wdoi
10.1016/j.xphs.2020.01.008subject
Has Abstractpub_date
2020-04-01 00:00:00pages
1615-1622issue
4eissn
0022-3549issn
1520-6017pii
S0022-3549(20)30013-7journal_volume
109pub_type
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abstract::Levetiracetam therapy is often associated with high levels of individual variation in the recommended dose required to achieve preferential treatment. Thus, a reliable and dynamic regulation system to accurately tailor dose is necessary. The main objective of this study is to explore and prepare a dose-flexible contro...
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abstract::To evaluate the regional delivery of conventional aerosol medications, a new whole-lung computational fluid dynamics modeling approach was applied for metered dose inhaler (MDI) and dry powder inhaler (DPI) aerosols delivered to healthy and constricted airways. The computational fluid dynamics approach included comple...
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journal_title:Journal of pharmaceutical sciences
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journal_title:Journal of pharmaceutical sciences
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journal_title:Journal of pharmaceutical sciences
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abstract::The pharmacokinetics of aniracetam (AP), a new cognitive performance enhancer, and its main metabolites was investigated after intravenous (iv) and oral administrations to rat. The plasma levels of AP, 4-p-anisamidobutyric acid (ABA), and p-anisic acid (AA) were determined simultaneously by the HPLC method. The plasma...
journal_title:Journal of pharmaceutical sciences
pub_type: 杂志文章
doi:10.1021/js970355p
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abstract::A simple and sensitive method is reported for the quantitative determination of the bronchodilator tulobuterol in human serum. Tulobuterol and an internal standard were extracted from alkalinized serum with ether and then back-extracted into dilute hydrochloric acid. After alkalinization and extraction of the aqueous ...
journal_title:Journal of pharmaceutical sciences
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abstract::Complex dosing regimens simulated in the literature using a universal dosing regimen were calculated with a general dosing program developed using the program CONSAM. The program provides a rapid method of calculating nonuniform dosing regimens for up to n = 3 compartments for any linear model. Subject data can also b...
journal_title:Journal of pharmaceutical sciences
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abstract::A series of even numbered fatty acid esters (C2-C18) of p-[N,N-bis(2-chloroethyl)amino]phenol were synthesized and evaluated as to acute toxicity as well as effectiveness against L-1210 mouse leukemia. The acetate through the decanoate derivatives demonstrated toxicity between 2 and 3 times that of phenol mustard in H...
journal_title:Journal of pharmaceutical sciences
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abstract::A novel in-line technique utilising pulsed terahertz radiation for direct measurement of the film coating thickness of individual tablets during the coating process was previously developed and demonstrated on a production-scale coater. Here, we use this technique to monitor the evolution of tablet film coating thickn...
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abstract::The synthesis, hydrolysis rate, and bioavailability of 1-(p-acetaminophenoxy)-1-ethoxyethane, an acetaminophen prodrug, are described. The prodrug is less soluble than acetaminophen and stable at neutral pH. However, in an acidic environment, the compound cleaves rapidly, generating acetaminophen. When both the prodru...
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