Pemetrexed-loaded supramolecular acetal-functionalized pH-responsive nanocarriers selectively induce apoptosis through biotin receptors to enhance antitumor efficacy.

Autor: Marwaha D; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, UP 201002, India., Singh N; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Gautam S; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Rai N; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Tiwari P; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Bakshi AK; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Kumar A; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Agarwal N; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Sharma M; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Shukla RP; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India., Mishra PR; Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute, Lucknow, UP 226031, India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, UP 201002, India. Electronic address: mishrapr@hotmail.com.
Jazyk: angličtina
Zdroj: Colloids and surfaces. B, Biointerfaces [Colloids Surf B Biointerfaces] 2024 Sep 21; Vol. 245, pp. 114247. Date of Electronic Publication: 2024 Sep 21.
DOI: 10.1016/j.colsurfb.2024.114247
Abstrakt: A novel pH-responsive crystalsomes has been developed using acetal-functionalized pillar[5]arenes (AP[5]) and methyl viologen (MV) through host-guest interactions. The successful synthesis of AP[5] was confirmed via 1 H-NMR spectroscopy, while the formation of the host-guest complex between AP[5] and MV was also verified using ¹H-NMR. The supramolecular assemblies formed at a 1:1 molar ratio of AP[5] to MV exhibited remarkable colloidal stability, a negative surface charge, and a high association constant.An acetal-functionalized pillara[5]arenes (AP[5]) crystalsomes were fabricated to reduce the toxicity of pemetrexed (PMX) in off-target sites and deliver the therapeutic doses to the active sites. Extensive characterization of the crystalsomes was performed, revealing their morphology and crystalline structure through SEM and TEM imaging. WAXS analysis confirmed the crystalline nature of the assemblies, and SAED patterns indicated that the crystalsome shell consisted of lamellae resembling single crystals with polymer chains oriented parallel to the interface. To enhnace the targeting capabilities, the surface of the crystalsomes was modified with biotin by conjugating viologen with biotin (MV-BT), aiming to target biotin receptors overexpressed on tumor cells. These biotin -modified crystalsomes (PMX-BT@CLs) were designed to be acid-labile facilitating the release of encapsulated drugs upon cellular internalization, as confirmed by confocal laser scanning microscopy (CLSM). In vivo, studies demonstrated that the PMX-loaded crystalsomes remained in circulation for extended period, showing improved pharmacokinetics. The area under the curve (AUC) of PMX-BT@CLs was approxiately 3.9 times higher than that of the free drug. Additionally, the relative tumor volume was found to be about 3.5 times lower in the group treated with biotin-modified crystalsomes compared to those treated with free PMX. The mean survival time was also significantly enhanced in the PMX-BT@CLs group. This study underscores the potential of using host-guest motifs in drug delivery app;ications, demonstrating the PMX can effectively targted to tumor sites with minimal off-target toxicity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no financial or personal conflicts that might look to have influenced the research. CDRI communication number for this manuscript 189/2023/PRM.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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