Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications
Abstract
:1. Introduction
2. Charge-Reversal Nano-Drug Delivery System
2.1. pH-Responsive Charge-Reversal Systems
2.1.1. Cleavage of Chemical Bonds
2.1.2. Protonation and Deprotonation of Functional Groups
2.2. Redox-Sensitive Charge-Reversal Systems
2.2.1. ROS-Sensitive Charge-Reversal System
2.2.2. GSH-Sensitive Charge-Reversal System
2.3. Enzyme-Responsive Charge-Reversal Systems
2.3.1. MMP-Responsive Charge-Reversal System
2.3.2. APN-Responsive Charge-Reversal System
2.3.3. GGT-Responsive Charge-Reversal System
2.3.4. HAase-Responsive Charge-Reversal System
3. Applications of Charge-Reversal Systems
3.1. Drug Delivery in Chemotherapy
3.2. Dual- and Multi-Responsive CRNDDSs
3.3. Gene-Delivery Therapy
3.4. Chemo-Photothermal Therapy
3.5. Contrast Agents Delivery
3.6. Other Treatment Modalities Combined with CRNDDSs
4. Limitations of CRNDDSs
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stimulus | Responsive Component | Reference |
---|---|---|
pH/ROS | 2,3-dimethylmaleic anhydride (DMA); thioketal (TK) | [88] |
pH/GSH | tertiary amine groups; disulfide bond | [44] |
benzoic-imine bond; disulfide bond | [31] | |
ROS/pH | thioketal (TK); PBAE | [43] |
pH/pH | β-carboxylic amide; Schiff base | [89] |
Histidine; hexahydrobenzoic amide | [90] | |
pH/MMP-2 | PEG-His; MMP-2 response peptide (PLGVRKLVFF) | [48] |
pH/MMP-9 | poly((1,4-butanediol)-diacrylate-β-N,N-diisopropylethyl-enediamine)-polyethyleneimine (BD-PEI); poly((1,4-butanediol)-diacrylate-β-N,N-diisopropylethylenediamine)-PLG-PEG (BD-PLG-PEG) | [69] |
Thermal/pH/redox | poly(N-isopropylacrylamide) (PNIPAM); cystamine; phosphate groups | [91] |
Treatment Modalities | Charge Reversal Stimulus | Advantages | Reference |
---|---|---|---|
Immunotherapy | pH/redox | Programmable drug delivery and chemotherapy-enhanced indoleamine 2,3-dioxygenase (IDO) immunotherapy strategy | [113] |
Immunotherapy | ROS | Starvation/oxidation-integrated IDO blockade immunotherapy | [114] |
Immunotherapy and PDT | MMP2/GSH | PDT combined ICB therapy, performing MR and μCT imaging in vivo | [108] |
Immunotherapy | pH | Excellent synergistic inhibitory effect on B16-F10 tumor growth | [86] |
Immunotherapy | photo | Achieving photo-enhanced intracellular delivery of Ce6 and iFSP1 to induce synergistic ferroptosis, thereby leading to ICD | [115] |
Immunotherapy and PDT | pH/MMP2 | Improving the immuno-photodynamic therapeutic effect and alleviating the immune-related adverse events | [116] |
Treatment Modalities | Charge Reversal Stimulus | Effect | Advantages | Limits | Reference |
---|---|---|---|---|---|
Immunotherapy | pH | TAMs repolarized to the M1 type | The first combination of charge-reversal polymers and OMVs used to realize a separation function | Further research is needed on the internal mechanism of charge-reversal polymer-induced vesicle destruction | [25] |
Immunotherapy | pH | Re-educate M2-TAMs to the M1 phenotype | Delivering siVEGF and siPIGF to both M2-TAMs and breast cancer cells for synergistic anti-tumor immunotherapy | [120] | |
Immunotherapy | pH | Repolarizing M2-TAMs and inducing the ICD | Demonstrating the best anti-tumor effect in vivo and suppressing MDSCs and Tregs to further reconstruct the ITM | [110] | |
Immunotherapy | pH | Induced cell cycle arrest, enhanced TAM repolarization, inhibited Treg cell function | Utilizing the novel triple-interlocked combination therapy on chemotherapy, immunotherapy, and chemoimmunotherapy | [121] | |
Immunotherapy | pH | Inhibiting immune cell recruitment and pro-inflammatory factors stimulus | Emerging strategies of immunotherapy for the prevention and treatment of atherosclerosis | [122] |
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Liang, Y.; Wu, J.; Yan, Y.; Wang, Y.; Zhao, H.; Wang, X.; Chang, S.; Li, S. Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications. Int. J. Mol. Sci. 2024, 25, 9779. https://doi.org/10.3390/ijms25189779
Liang Y, Wu J, Yan Y, Wang Y, Zhao H, Wang X, Chang S, Li S. Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications. International Journal of Molecular Sciences. 2024; 25(18):9779. https://doi.org/10.3390/ijms25189779
Chicago/Turabian StyleLiang, Yizhu, Jiashuai Wu, Yutong Yan, Yunduan Wang, Hongtu Zhao, Xiaopeng Wang, Shijie Chang, and Shuo Li. 2024. "Charge-Reversal Nano-Drug Delivery Systems in the Tumor Microenvironment: Mechanisms, Challenges, and Therapeutic Applications" International Journal of Molecular Sciences 25, no. 18: 9779. https://doi.org/10.3390/ijms25189779