Tumor acidity-induced surface charge modulation in covalent nanonetworks for activated cellular uptake: targeted delivery of anticancer drugs and selective cancer cell death

Santra, Subrata; Das, Sanjoy; Sengupta, Arunima; Molla, Mijanur Rahaman

doi:10.1039/d3bm00491k

Cited by 9 publications

(9 citation statements)

References 89 publications

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“…20–22 Even though numerous pH-triggered drug-delivery systems have been developed, most have focused on the responsiveness to intracellular pH. 23–30 Less attention has been paid to the development of nanocarriers that can respond sensitively to the acidic extracellular environment of the tumor because of the slight pH change (from 7.4 to 6.8), relatively weak acidity, and structure limitation. 31–34 Currently, only maleic acid amides, 34,35 hydrazones, 36,37 imines, 38,39 and sulfonamides 40–44 have been reported with regard to responsiveness to the weak acidic environment.…”

Section: Introductionmentioning

confidence: 99%

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity

Xu,

Ma,

Wang

et al. 2024

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity

Xu,

Ma,

Wang

et al. 2024

Chem. Sci.

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“…Thus, the nanocarrier results in the release of guest molecules in a sustained manner, which allows controlled drug delivery. More importantly, the additional advantage of this linker is that the ease of generation by a facile thiol–acrylate Michael reaction in the presence of a phosphine catalyst. , Moreover, this cross-linked nanocarrier undergoes surface charge modulation from neutral to positive at gentle acidic pH, relevant to tumor extracellular matrix (pH ∼ 6.4–6.8). , Hence, the use of this cross-linked nanocarrier could be a good option for tumor-microenvironment-acidity-mediated targeted cancer drug delivery. − The strategy of cross-linking the core region of a self-assembled nanocarrier system has already shown many advantages compared to uncross-linked nanocarrier − such as (a) tolerance of dilution effect and therefore improving nanocarrier stability; (b) lowering of drug leakiness; (c) minimization of premature drug release and therefore no side effect caused by off-targeting; and (d) modulation in the drug release behavior, i.e., controlled release. Here, we have used this system as a potential drug carrier for sesquiterpene lactone-based anticancer agent parthenolide (PTL).…”

Section: Introductionmentioning

confidence: 99%

Poly-β-thioester-Based Cross-Linked Nanocarrier for Cancer Cell Selectivity over Normal Cells and Cellular Apoptosis by Triggered Release of Parthenolide, an Anticancer Drug

Dey,

Mondal,

Aash

et al. 2024

ACS Appl. Bio Mater.

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Breast cancer is the most prevalent and aggressive type of cancer, causing high mortality rates in women globally. Many drawbacks and side effects of the current chemotherapy force us to develop a robust chemotherapeutic system that can deal with off-target hazards and selectively combat cancer growth, invasiveness, and cancer-initiating cells. Here, a pH-responsive cross-linked nanocarrier (140–160 nm) endowed with poly-β-thioester functionality (CBAPTL) has been sketched and fabricated for noncovalent firm encapsulation of anticancer drug, parthenolide (PTL) at physiological pH (7.4), which enables sustain release of PTL at relevant endosomal pH (∼5.0–5.3). For this, a bolaamphiphilic molecule integrated with β-thioester and acrylate functionality was synthesized to fabricate the pH-responsive poly-β-thioester-based cross-linked nanocarrier via Michael addition click reactions in water. The poly-β-thioester functionality of CBAPTL hydrolyzes at endosomal acidic conditions, thus leading to the selective release of PTL inside the cancer cell. Cross-linked nanocarriers exhibit high serum stability, dilution insensitivity, and targeted cellular uptake at tumor microenvironment (TME), contrasting normal cells. In vitro study using human MCF-7 breast cancer cells demonstrated that CBAPTL exhibited selective cytotoxicity, reduced clonogenic potential, increased reactive oxygen species (ROS) generation, and arrested the progression of the cell cycle at the G0/G1 phase efficiently. CBAPTL induced apoptosis via downregulating pro-proliferative protein Bcl-2 and upregulating proapoptotic proteins p53, BAD, p21, and cleaved PARP-1. CBAPTL inhibited proliferating signaling by suppressing AKT phosphorylation and p38 expression. CBAPTL also blocked the invasion and migration of MCF-7 cells. CBAPTL effectively inhibits primary and secondary mammosphere formation, thereby preventing cancer-initiating cells’ growth. Conversely, CBAPTL has negligible effect on human red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs). These findings highlight the superior efficacy of CBAPTL compared to PTL alone in suppressing cancer cell growth, inducing apoptosis, and preventing invasiveness of MCF-7 cells. Thus, CBAPTL could be considered a possible selective chemotherapeutic cargo against breast cancer without affecting normal cells.

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“…Polymeric material-based nanoassemblies such as micelles, − vesicles, − and liposomes − are widely used as drug carriers due to their enhanced kinetic and thermodynamic stability compared to small-molecule-based assemblies. They hold the promise to keep the sequestered drug molecules safe under one set of conditions and release them under another in response to physiological stimuli such as pH, − light, − hypoxia, − redox, − temperature, − enzymes, , etc. The stimuli-responsive functionality has been installed on the polymeric structure for location-specific triggered guest release, thus overcoming the poor selectivity and severe side effects of chemotherapeutic treatments.…”

Section: Introductionmentioning

confidence: 99%

Degradable Polymer-Based Nanoassemblies for Precise Targeting and Drug Delivery to Breast Cancer Cells without Affecting Normal Healthy Cells

Santra,

Das,

Dey

et al. 2024

Biomacromolecules

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Stimuli-responsive amphiphilic polymers are known to be precursors to forming promising nanoarchitectonics with tunable properties for application in biomedical sciences. Currently, self-immolative polymers are widely recognized as an emerging class of responsive materials with excellent degradability, which is one of the crucial criteria for designing a robust drug delivery vehicle. Here, we design an amphiphilic polyurethane endowed with a redox-responsive self-immolative linker and a pH-responsive tertiary amine on the backbone, which forms entropy-driven nanoscale supramolecular assemblies (average hydrodynamic diameter ∼110 nm) and is programmed to disassemble in a redox environment (GSH) due to the degradation of the polymer in a selfimmolative fashion. The nanoassembly shows efficient drug sequestration and release in a controlled manner in response to glutathione (10 mM). The tertiary amine residing on the surface of the nanoassembly becomes protonated in the tumor microenvironment (pH ∼ 6.4−6.8) and generates positively charged nanoassembly (ζ-potential = +36 mV), which enhances the cancer cell-selective cellular uptake. The biological evaluation of the drug-loaded nanoassembly revealed triple-negative breast cancer (MDAMB-231) selective internalization and cell death while shielding normal cells (RBCs or PBMCs) from off-targeting toxicity. We envision that polyurethane with a redox-responsive self-immolative linker might open up new opportunities for a completely degradable polyurethane-based nanocarrier for drug delivery and diagnosis applications.

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Tumor acidity-induced surface charge modulation in covalent nanonetworks for activated cellular uptake: targeted delivery of anticancer drugs and selective cancer cell death

Abstract: A β-thioester and tertiary amine based covalently cross-linked nanoassembly coined as nanonetwork (NN) endowed with dual pH responsive features, (tumor acidity induced surface charge modulation and endosomal pH triggered controlled...

Cited by 9 publications

References 89 publications

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity

N-Sulfonyl amidine polypeptides: new polymeric biomaterials with conformation transition responsive to tumor acidity

Poly-β-thioester-Based Cross-Linked Nanocarrier for Cancer Cell Selectivity over Normal Cells and Cellular Apoptosis by Triggered Release of Parthenolide, an Anticancer Drug

Degradable Polymer-Based Nanoassemblies for Precise Targeting and Drug Delivery to Breast Cancer Cells without Affecting Normal Healthy Cells

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