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backbone, side chains, on the surface, etc. Research has been conducted with reduction sensitivity mechanisms using polymeric, lipid-polymer hybrids, and micelles nanoparticles. The production methods would be dependent on the delivery method design for the nanoparticle. Polymeric nanoparticle synthesis occurs from the addition of electrolyte-saturated or a nonelectrolyte-saturated solution with a water-miscible solvent; additionally, the mixture should be constantly stirred. Lipid micelles are formed by amphiphilic molecules through self-assembly. Lipid-polymer hybrids have multiple synthesis methods which consist of the single-step method, the two-step method, nanoprecipitation, emulsification-solvent evaporation, and a non-conventional two-step method.
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the cytosol and cell nucleus. Furthermore, drug release in the cytosol and cell nucleus has shown the potential to effectively administer treatment of more potent and poorly soluble anticancer drugs. The quick-release of RSNPs has the potential to offer an effective treatment for multidrug-resistant tumors. This addresses an important limitation of nanoparticles. Nanoparticle drug delivery often exhibits slow drug release. The slow release can lead the nanomedicine to be released at low concentrations; moreover, these limited concentrations inhibit the cell death of the tumor cells. Polymeric RSNPs have shown improved solubility, stability, biocompatibility, and decreased drug toxicity; for example, carbohydrate polymers.
92:(TME). Nanoparticles can be synthesized to activate when exposed to selective characteristics of the tumor microenvironments. TMEs depict unique characteristics that create a differing microenvironment in comparison to healthy tissue. Thus, nanoparticles can be designed to react to the unique elements of TMEs such as the formation of a reducing environment. The reducing abilities of the TMEs are due to the expression of reducing agents. RSNPs are formulated to express reduction-sensitive bonds that are cleaved when exposed to reducing agents. After the reduction occurs the degradation of the nanoparticles commences and the loaded drugs begin to release.
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312:
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RSNPs are designed to be receptive to higher concentrations of reducing agents for the ability to distinguish between cancer cells and healthy cells. Furthermore, the other limitations are dependent on other characterizations, such as the type of nanoparticle; For example, micelles nanoparticles' lower levels of physical stability which can lead to drug loss and release in unwanted locations. Additionally, polymeric nanoparticles cannot effectively target the tumor and often undergo drug release too early.
211:
cleaved. Following the activation process, the degradation of the drug carrier results in the drug release. These linkages are commonly used between hydrophilic and hydrophobic segments in copolymers. Moreover, RSNP's hydrophilic shells will degrade in response to the reducing environment. The disulfide bonds are used as linkers and cross-linking agents. Disulfide bonds can be expressed attached to the side chains, the backbone, on the surface, and as linkages between moieties.
106:
as a polymeric, micelle, or lipid-polymeric hybrid. The reduction sensitivity of nanoparticles is reliant on the reduction-responsive chemical structures infused into the nanoparticle. Reduction occurs when the number of electrons increases in a chemical species. Reduction sensitive nanoparticles depict high plasma stability and quick responsiveness/activation. The reducing environment of tumor cells is greatly impacted by the oxidation and reduction states of
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304:
conducted to evaluate the potential of RSNP as a therapeutic for inflammatory bowel disease. The activation mechanism consisted of pH and redox sensitivity. The outcomes of the experiment demonstrated higher selectivity to the reducing potential; therefore establishing the promising potential of RSNPs for the treatment of inflammatory bowel disease. Other studies have demonstrated potential applications as activatable magnetic resonance
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20:
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could result in undertreatment of tumor cells with little to no effect. Concentration thresholds must be met to initiate cell death amongst tumor cells. However, the uncontrolled release of treatment could also permit adverse side effects. RSNPs have improved rates of drug release which improves the medication concentrations that can be administered to a specific area.
38:. Drug delivery systems using RSNP can be loaded with different drugs that are designed to be released within a concentrated reducing environment, such as the tumor-targeted microenvironment. Reduction-Sensitive Nanoparticles provide an efficient method of targeted drug delivery for the improved controlled release of medication within localized areas of the body.
295:
RSNPS can also increase the penetration of cancer treatment to the cancer cells. Specific applications include, but are not limited to Breast Cancer, Liver Cancer (hepatoma), Melanoma, Lung Cancer, Malignant Glioma, Ovarian Cancer, Cervical Cancer, Subcutaneous EAT, Pancreatic Cancer, Colon Cancer, Prostate Cancer, etc.
236:
and disulfide bonds have estimated bond energy of 268 kJ/mol; the lower bond energy holds a higher potential to design an increased sensitive redox-responsive delivery. Diselenide bonds have been observed to be attached to hydrophobic parts of amphiphilic triblocks or hyperbranched copolymers to create micelles.
175:
that is naturally produced in the liver and takes part in tissue building, tissue repair, immune responses, chemical production, and protein production. GSH is also a significant signaler of cell differentiation, proliferation, apoptosis, and ferroptosis. Furthermore, the glutathione concentration in
58:
in the localized area. The cleavage/degradation of chemical bonds will enable the drugs loaded within the nanoparticle to be released into the body. Depending on the activation mechanism, Redox-Sensitive
Nanoparticles can be associated with Reduction-Sensitive Nanoparticles if the chemical activation
49:
are small in size with maximized surface area and have an enhanced level of solubility; these elements result in an improved bioavailability. Reduction-Sensitive
Nanoparticles are nanoparticles that are responsive to reduction signaling environments. Redox-Sensitive Nanoparticles can be responsive to
271:
Reduction
Sensitive Nanoparticles provide a mode of localized drug delivery by targeting elements of the tumor microenvironment. RSNP has the advantages of high stability when adhering to hydraulic degradation, fast responsiveness to the intracellular reducing environment, and drug release occurs in
235:
bonds share comparable reduction responsiveness to disulfide bonds. Diselenide consists of two selenium atoms along with an additional element or radical. Diselenide bonds are dynamic covalent bonds that can be exchange between molecules. Diselenide bonds have an estimated bond energy of 172 kJ/mol,
214:
Disulfide bonds can also act as cross-linking agents in micelles nanoparticles. Micelles lack the structural stability as a nanocarrier for drug delivery. The lack of stability can result in the loss of drugs after administration and before reaching the infected area. This occurrence can potentially
105:
The physicochemical characteristics of nanoparticles are inclusive of the size, shape, chemical composition, stability, topography, surface charge, and surface area. Deviations of these characteristics can be impacted by the classification of the nanoparticle. For example, the RSNP can be classified
262:
The synthesis of reduction sensitive nanoparticles is dependent on the mechanism subtype of the nanoparticle. Additionally, the synthesis can vary within subtype classes depending on how the different reduction sensitive bonds are expressed. The deviations of RSNPs can range from attachments to the
244:
Succinimide-thioether linkages express sensitivity to reducing environments and can be cleaved as a result. Succinimide-thioether bonds show slower rates of release in comparison to disulfide bonds; however, succinimide-thioether nanoparticles are still sensitive to the reducing environment and are
210:
are commonly observed in medical research. RSNP can consist of disulfide bonds that are cleaved and introduced to a reduction condition. Additionally, the reduction of glutathione results in the formation of sulfhydryl groups. In large concentrations of GSH, the disulfide bonds are capable of being
179:
The over-expression of nicotinamide adenine dinucleotide phosphate NADPH can lead to higher ROS levels. NADPH has a lower concentration than GSH in the reducing environment. NADPH is an electron donor that exists among all organisms; additionally, the NADPH is used as a source of reduction to drive
280:
The effectiveness of reduction-sensitive nanoparticles is dependent on the responsiveness of the RSNP throughout the body. The microtumor and inflammatory environments contain higher concentrations of reducing agents in contrast to healthy cells; however, healthy cells still express GSH and NADPH.
294:
Reduction
Sensitive Nanoparticles are used as nanomedicines for drug delivery. As nanocarriers, RSNP can be loaded with drugs for disease therapeutics. This is commonly observed in the use of tumor and cancer treatments. Cancer cells create reducing environments that are used for RSNP activation.
84:
One of the limitations of nanoparticles for drug delivery is the insufficient or slow release of drugs. The rate of release is a critical element to identify how slowed drug release could limit the proper concentration of treatment. If the drug is not administered in concentrations high enough it
303:
The development of RSNP for inflammatory diseases has been explored to a lesser extent. Regardless, in more recent years reduction-sensitive and redox-sensitive nanoparticles have gained more momentum in the realm of inflammatory diseases. Further advances have demonstrated
Research has been
67:
Nanoparticle Drug
Loading is dependent on the mass ratio of the drug being loaded and the drug-loaded nanoparticle. Variations necessary to consider are the pore volume size, the surface, shape, and charge of the nanoparticle. The mode of drug loading will depend on the type of drug being
398:
Yin, Huabin; Meng, Tong; Shu, Ling; Mao, Min; Zhou, Lei; Chen, Haiyan; Song, Dianwen (2017-06-04). "Novel reduction-sensitive micellar nanoparticles assembled from
Rituximab-doxorubicin conjugates as smart and intuitive drug delivery systems for the treatment of non-Hodgkin's lymphoma".
1409:
He, Mengxue; Yu, Ling; Yang, Yuanyuan; Zou, Binhua; Ma, Wen; Yu, Meng; Lu, Jiandong; Xiong, Guoliang; Yu, Zhiqiang; Li, Aimin (December 2020). "Delivery of triptolide with reduction-sensitive polymer nanoparticles for liver cancer therapy on patient-derived xenografts models".
215:
cause adverse side effects from the improper release of medication. Disulfide bonds can be used as crosslinked structures to increase the structural stability of micelle nanocarriers. In general, these crosslinks are located in the shell or the core of micelles nanoparticles.
180:
anabolic reactions and redox balances. The reduction and oxidation states of NADPH/NADP+ will influence the reduced responsiveness of the environment. Cancer cells express a unique NADPH homeostasis due to the adaptive alterations of signaling pathways and metabolic enzymes.
1569:
Sun, Qijuan; Luan, Lin; Arif, Muhammad; Li, Jiaxin; Dong, Quan-Jiang; Gao, Yuanyuan; Chi, Zhe; Liu, Chen-Guang (June 2018). "Redox-sensitive nanoparticles based on 4-aminothiophenol-carboxymethyl inulin conjugate for budesonide delivery in inflammatory bowel diseases".
1621:
Han, Shou-Chen; He, Wei-Dong; Li, Jian; Li, Li-Ying; Sun, Xiao-Li; Zhang, Bo-Yu; Pan, Ting-Ting (2009-07-08). "Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis, properties, and
1127:
Kanwal, Sidra; Naveed, Muhammad; Arshad, Ali; Arshad, Azka; Firdous, Farhat; Faisal, Amir; Yameen, Basit (2021-11-11). "Reduction-Sensitive
Dextran–Paclitaxel Polymer–Drug Conjugate: Synthesis, Self-Assembly into Nanoparticles, and In Vitro Anticancer Efficacy".
253:
Nanoparticles with
Trimethyl Benzoquinone have demonstrated responsiveness to reduced environments. The experiments that have been conducted testing TMBQ are limited in observing the full scope of TMBQ nanoparticles in delivery systems.
627:
Wu, Bo; Yu, Ping; Cui, Can; Wu, Ming; Zhang, Yang; Liu, Lei; Wang, Cai-Xia; Zhuo, Ren-Xi; Huang, Shi-Wen (2015). "Folate-containing reduction-sensitive lipid–polymer hybrid nanoparticles for targeted delivery of doxorubicin".
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homeostasis leading to differences in the redox balance and increases in ROS levels. Research trends have shown that increased levels of ROS are correlated with high levels of antioxidant activity, such as intracellular GSH.
513:
Mirhadi, Elaheh; Mashreghi, Mohammad; Faal Maleki, Mahdi; Alavizadeh, Seyedeh Hoda; Arabi, Leila; Badiee, Ali; Jaafari, Mahmoud Reza (November 2020). "Redox-sensitive nanoscale drug delivery systems for cancer treatment".
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Sun, Haifeng; Cao, Dinglingge; Liu, Yanhong; Wang, Hui; Ke, Xue; Ci, Tianyuan (2018). "Low molecular weight heparin-based reduction-sensitive nanoparticles for antitumor and anti-metastasis of orthotopic breast cancer".
333:
Zielińska, Aleksandra; Carreiró, Filipa; Oliveira, Ana M.; Neves, Andreia; Pires, Bárbara; Venkatesh, D. Nagasamy; Durazzo, Alessandra; Lucarini, Massimo; Eder, Piotr; Silva, Amélia M.; Santini, Antonello (2020-08-15).
922:
Yu, Jiahui; Fan, Honglei; Huang, Jin; Chen, Jinghua (2011). "Fabrication and evaluation of reduction-sensitive supramolecular hydrogel based on cyclodextrin/polymer inclusion for injectable drug-carrier application".
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the tumor microenvironment is reportedly at least four times higher compared to regular tissue. This is due to the high metabolic needs of tumor cells; for example, the rapid proliferation rates of tumor cells.
1179:
Sun, Huanli; Meng, Fenghua; Cheng, Ru; Deng, Chao; Zhong, Zhiyuan (2013-03-22). "Reduction-sensitive degradable micellar nanoparticles as smart and intuitive delivery systems for cancer chemotherapy".
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Yang, Jinlong; Huang, Yinjuan; Gao, Chunmei; Liu, Mingzhu; Zhang, Xinjie (March 2014). "Fabrication and evaluation of the novel reduction-sensitive starch nanoparticles for controlled drug release".
122:
For the effective application of RSNPs, the physicochemical characteristics of the tumor microenvironment must also be considered. The characteristics depicted by the TME are
163:
Glutathione (GSH) or Îł-glutamyl-cysteinyl-glycine is a critical biological reducing agent for drug delivery applications; it creates an effective reducing environment in the
736:
Sun, Huanli; Zhang, Yifan; Zhong, Zhiyuan (July 2018). "Reduction-sensitive polymeric nanomedicines: An emerging multifunctional platform for targeted cancer therapy".
1070:"Codelivery of doxorubicin and triptolide with reduction-sensitive lipid–polymer hybrid nanoparticles for in vitro and in vivo synergistic cancer treatment"
676:"Lipid polymer hybrid nanocarriers: Insights into synthesis aspects, characterization, release mechanisms, surface functionalization and potential implications"
1332:
Bhaw-Luximon, Archana; Goonoo, Nowsheen; Jhurry, Dhanjay (2016). "Nanotherapeutics promises for colorectal cancer and pancreatic ductal adenocarcinoma".
1273:
Yao, Yihan; Zhou, Yunxiang; Liu, Lihong; Xu, Yanyan; Chen, Qiang; Wang, Yali; Wu, Shijie; Deng, Yongchuan; Zhang, Jianmin; Shao, Anwen (2020-08-20).
966:
Ma, Ning; Li, Ying; Xu, Huaping; Wang, Zhiqiang; Zhang, Xi (2009-12-18). "Dual Redox
Responsive Assemblies Formed from Diselenide Block Copolymers".
1512:"Activatable Nanoparticles: Recent Advances in Redox-Sensitive Magnetic Resonance Contrast Agent Candidates Capable of Detecting Inflammation"
50:
signaling through a reduction activation or an oxidative activation. Therefore, degradation of chemical bonds can be either activated through
88:
RSNPs consist of reduction or redox-sensitive bonds. After administration in the body, the RSNP will eventually come into contact with the
1675:
107:
142:(ROS), etc. The elements of the tumor microenvironment can affect the reduction-inducing environment. Tumor cells abnormally regulate
308:. These proposed agents would help detect and monitor the treatment of inflammatory diseases by applying redox dysregulation.
1011:"Development of a reduction-sensitive diselenide-conjugated oligoethylenimine nanoparticulate system as a gene carrier"
1349:
565:
Gatoo, Manzoor Ahmad; Naseem, Sufia; Arfat, Mir Yasir; Mahmood Dar, Ayaz; Qasim, Khusro; Zubair, Swaleha (2014).
674:
Shah, Saurabh; Famta, Paras; Raghuvanshi, Rajeev Singh; Singh, Shashi Bala; Srivastava, Saurabh (January 2022).
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806:
Guo, Xiaoshuang; Cheng, Yuan; Zhao, Xiaotian; Luo, Yanli; Chen, Jianjun; Yuan, Wei-En (2018-09-22).
451:
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Nwasike, Chukwuazam; Purr, Erin; Yoo, Eunsoo; Nagi, Jaspreet Singh; Doiron, Amber L. (2021-01-16).
139:
1275:"Nanoparticle-Based Drug Delivery in Cancer Therapy and Its Role in Overcoming Drug Resistance"
89:
1068:
Wu, Bo; Lu, Shu-Ting; Zhang, Liu-Jie; Zhuo, Ren-Xi; Xu, Hai-Bo; Huang, Shi-Wen (March 2017).
567:"Physicochemical Properties of Nanomaterials: Implication in Associated Toxic Manifestations"
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Ju, Huai-Qiang; Lin, Jin-Fei; Tian, Tian; Xie, Dan; Xu, Rui-Hua (2020-10-07).
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808:"Advances in redox-responsive drug delivery systems of tumor microenvironment"
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Liu, Yun; Yang, Guangze; Jin, Song; Xu, Letao; Zhao, Chun-Xia (2020-08-31).
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administered, which will vary depending on the illness that is treated.
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Redox sensitive nanoparticles vs. reduction sensitive nanoparticles
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Fig. 4.0 Drug Release of RSNP with Disulfide Bonds in the Cytosol
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Journal of Polymer Science Part A: Polymer Chemistry
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452:"Development of High-Drug-Loading Nanoparticles"
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315:Fig. 6.0 Ulcerative Colitis VS. Crohn's Disease
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245:cleaved by GSH for fast intracellular release.
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1453:Mocny, Piotr; Klok, Harm-Anton (2020-01-14).
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227:Fig. 5.0 Relevant Nanoparticle Subtypes
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1279:Frontiers in Molecular Biosciences
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571:BioMed Research International
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171:of a cell. Glutathione is an
59:method is through reduction.
1480:10.1021/acs.macromol.9b02199
1193:10.1517/17425247.2013.783009
812:Journal of Nanobiotechnology
693:10.1016/j.colcom.2021.100570
249:Trimethyl benzoquinone bonds
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1424:10.1016/j.cclet.2020.05.034
240:Succinimide-thioether bonds
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1009:Gu, Zhongwei (July 2012).
883:10.1038/s41392-020-00326-0
750:10.1016/j.addr.2018.05.007
825:10.1186/s12951-018-0398-2
353:10.3390/molecules25163731
189:Reduction sensitive bonds
63:Nanoparticle drug loading
1412:Chinese Chemical Letters
1292:10.3389/fmolb.2020.00193
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140:reactive oxygen species
1130:Bioconjugate Chemistry
471:10.1002/cplu.202000496
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90:tumor microenvironment
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1572:Carbohydrate Polymers
1336:. Elsevier: 147–201.
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299:Inflammatory diseases
258:Development/Synthesis
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630:Biomaterials Science
23:Fig. 1.0 Cancer Cell
16:Drug delivery method
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1471:2020MaMol..53..731M
1087:10.2147/ijn.s131235
937:2011SMat....7.7386Y
584:10.1155/2014/498420
1648:10.1002/pola.23468
1529:10.3390/ph14010069
1380:10.1039/c8bm00486b
1028:10.2147/ijn.s32961
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30:(RSNP) consist of
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1080:: 1853–1862.
1079:
1075:
1071:
1064:
1056:
1052:
1047:
1042:
1038:
1034:
1029:
1024:
1021:: 3991–4006.
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1016:
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989:
985:
981:
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48:
47:Nanoparticles
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931:(16): 7386.
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683:
679:
633:
629:
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459:ChemPlusChem
458:
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346:(16): 3731.
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279:
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178:
162:
128:angiogenesis
121:
104:
87:
83:
72:Drug Release
66:
45:
32:nanocarriers
27:
26:
1578:: 352–359.
1238:: 368–376.
925:Soft Matter
276:Limitations
173:antioxidant
112:Glutathione
110:/NADP+ and
1670:Categories
1626:release".
877:(1): 231.
686:: 100570.
577:: 498420.
522:: 119882.
320:References
267:Advantages
233:Diselenide
132:metabolism
56:reductants
1656:0887-624X
1592:0144-8617
1538:1424-8247
1522:(1): 69.
1497:213510887
1489:0024-9297
1440:219742385
1432:1001-8417
1388:2047-4830
1301:2296-889X
1252:0927-7765
1201:1742-5247
1166:244040558
1150:1043-1802
1096:1178-2013
1037:1178-2013
988:0002-7863
953:1744-683X
891:2059-3635
834:1477-3155
818:(1): 74.
758:0169-409X
744:: 16–32.
710:245472939
702:2215-0382
650:2047-4830
593:2314-6133
552:221786766
536:0378-5173
495:221382512
479:2192-6506
421:1747-0277
362:1420-3049
340:Molecules
36:reduction
1624:in vitro
1600:29580419
1556:33467028
1396:29942949
1319:32974385
1260:24463097
1217:22681173
1209:23517599
1158:34762796
1114:28331310
1055:22904624
996:20020681
909:33028807
852:30243297
774:21742380
766:29775625
658:26222425
611:25165707
544:32941986
487:32864902
437:21460046
429:28440948
380:32824172
184:Subtypes
136:acidosis
52:oxidants
1636:Bibcode
1608:4337453
1547:7829999
1467:Bibcode
1310:7468194
1285:: 193.
1105:5352248
1046:3418076
933:Bibcode
900:7542157
843:6151045
602:4140132
371:7464532
169:nucleus
165:cytosol
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368:
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1604:S2CID
1493:S2CID
1436:S2CID
1213:S2CID
1162:S2CID
770:S2CID
706:S2CID
548:S2CID
491:S2CID
455:(PDF)
433:S2CID
144:redox
108:NADPH
101:RSNPs
1652:ISSN
1596:PMID
1588:ISSN
1552:PMID
1534:ISSN
1485:ISSN
1428:ISSN
1392:PMID
1384:ISSN
1346:ISBN
1315:PMID
1297:ISSN
1256:PMID
1248:ISSN
1205:PMID
1197:ISSN
1154:PMID
1146:ISSN
1110:PMID
1092:ISSN
1051:PMID
1033:ISSN
992:PMID
984:ISSN
949:ISSN
905:PMID
887:ISSN
848:PMID
830:ISSN
762:PMID
754:ISSN
698:ISSN
654:PMID
646:ISSN
607:PMID
589:ISSN
575:2014
540:PMID
532:ISSN
483:PMID
475:ISSN
425:PMID
417:ISSN
376:PMID
358:ISSN
167:and
1644:doi
1580:doi
1576:189
1542:PMC
1524:doi
1475:doi
1420:doi
1376:doi
1338:doi
1305:PMC
1287:doi
1240:doi
1236:115
1189:doi
1138:doi
1100:PMC
1082:doi
1041:PMC
1023:doi
976:doi
972:132
941:doi
895:PMC
879:doi
838:PMC
820:doi
746:doi
742:132
688:doi
638:doi
597:PMC
579:doi
524:doi
520:589
467:doi
409:doi
366:PMC
348:doi
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Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
