Pathophysiology-Driven Approaches for Overcoming Nanomedicine Resistance in Pancreatic Cancer.

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Pharmaceutics Pub Date : 2024-11-19 DOI:10.1021/acs.molpharmaceut.4c00801

Sreejith Thrivikraman Nair, C Abhi, Kaladhar Kamalasanan, K Pavithran, Ashok R Unni, M S Sithara, Manjit Sarma, T S Mangalanandan

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Abstract

Tumor heterogeneity poses a significant challenge in cancer therapy. To address this, we analyze pharmacotherapeutic challenges by categorizing them into static and dynamic barriers, reframing these challenges to improve drug delivery, efficacy, and the development of controlled-release nanomedicines (CRNMs). This pathophysiology-driven approach facilitates the design of novel therapeutics tailored to overcome obstacles in pancreatic ductal adenocarcinoma (PDAC) using nanotechnology. Advanced biomaterials in nanodrug delivery systems offer innovative solutions by combining controlled release, stimuli sensitivity, and smart design strategies. CRNMs are engineered to modulate spatiotemporal signaling and control drug release in PDAC, where resistance to conventional therapies is particularly high. This review explores pharmacokinetic considerations for nanomedicine design, RNA interference (RNAi) for stromal modulation, and the development of targeted nanomedicine strategies. Additionally, we highlight the limitations of current animal models in capturing the complexities of PDAC and discuss notable clinical failures, such as PEGylated hyaluronidase (Phase III HALO 109-301 trial) and evofosfamide (TH-302) with gemcitabine (MAESTRO trial), underscoring the need for improved models and treatment strategies. By targeting pathways like Notch and Hedgehog and incorporating stimuli-sensitive and pathway-modulating agents, CRNMs offer a promising avenue to enhance drug penetration and efficacy, reshaping the paradigm of pancreatic cancer treatment.

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从病理生理学角度克服胰腺癌纳米药物抗药性的方法

肿瘤的异质性给癌症治疗带来了巨大挑战。为解决这一问题，我们分析了药物治疗面临的挑战，将其分为静态和动态障碍，重新构建这些挑战，以改善药物输送、疗效和控释纳米药物（CRNMs）的开发。这种以病理生理学为导向的方法有助于设计新型疗法，利用纳米技术克服胰腺导管腺癌（PDAC）的障碍。纳米给药系统中的先进生物材料结合了控释、刺激敏感性和智能设计策略，提供了创新的解决方案。CRNMs可调节时空信号传导并控制PDAC中的药物释放，而PDAC对传统疗法的耐药性特别高。本综述探讨了纳米药物设计的药代动力学考虑因素、用于基质调节的 RNA 干扰 (RNAi) 以及靶向纳米药物策略的开发。此外，我们还强调了当前动物模型在捕捉 PDAC 复杂性方面的局限性，并讨论了显著的临床失败，如 PEG 化透明质酸酶（HALO 109-301 III 期试验）和埃沃法胺（TH-302）与吉西他滨（MAESTRO 试验），强调了改进模型和治疗策略的必要性。CRNMs以Notch和刺猬等通路为靶点，并结合刺激敏感和通路调节药物，为增强药物渗透和疗效提供了一条前景广阔的途径，从而重塑了胰腺癌治疗模式。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.