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The Advantages and Versatility of Carrier-Free Nanodrug and Nanoparticle Systems for Cancer Therapy
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
There are various mechanisms for endosomal escape that facilitate the release of the therapeutic agents into the cytosol. Pore formation occurs through the interactions between the membrane tension that extends the pores and the line tension that closes the pores. This causes the forming of pores in the lipid bilayer mediated by aggregates of peptides that enter into the membrane in a perpendicular orientation, thus leading to an inward curving of the membrane. The proton sponge effect (pH-buffering effect) is a mechanism caused by the ability of agents to inflate when protonated. Through this step, called “protonation,” the entrapped components are released due to the inflow of ions and water into the endosomal environment, leading to endosomal membrane ruptures. Another mechanism is represented by the fusogenic peptides that have the ability to destabilize the endosomal membrane, which plays an important role in cellular trafficking and endocytosis. Endosomal membrane can be destroyed photochemically, by exposure to light. This method induces the formation of reactive singlet oxygen with a short lifetime which destroys the endosomal membrane, allowing the therapeutic agent to be delivered to the cytosol [223].
Preparation and characterization of polyamidoamine dendrimers conjugated with cholesteryl-dipeptide as gene carriers in HeLa cells
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Le Thi Thuy, Minyoung Choi, Minhyung Lee, Joon Sig Choi
Given that the proton sponge hypothesis explains the endosomal escape of cationic carriers, the protonation ability of the polymer is considered an important characteristic of gene carrier candidates. The high density of secondary or tertiary amines of PEI and PAMAM dendrimers contributes to the “proton sponge’’ effect. The buffering capacity of PEI inhibits lysosomal nuclease activity and changes the osmotic pressure of acidic vesicles, resulting in endosomal swelling and rupture [37]. In addition, PAMAM dendrimers contain protonable residues at physiological pH [38]. In this study, we evaluated the buffering capacity of PEI 25 kDa and PAMAM G2 derivatives using a titration method. As shown in Figure 2, PEI 25 kDa, PAMAM G2, PAMAM G2-HR, PAMAM G2-HRCHol 6%, and PAMAM G2-HRChol 23% dendrimers displayed significant buffering capacities. PEI 25 kDa had the strongest buffering capacity—due to the numerous amine groups that conferred a pKa between 8.5 and 9.5, thus allowing enhanced protonation at physiological pH. The lower number of amine groups around PAMAM G2 was responsible for its lower buffering capacity. Histidine contains an imidazole group (pKa around 6), which is protonated under acidic pH conditions. Therefore, we anticipated that the addition of histidine to the PAMAM G2 dendrimers could improve the buffering capacity. The results showed that PAMAM G2-HR, PAMAM G2-HRChol 6%, and PAMAM G2-HRChol 23% dendrimers displayed a higher buffering capacity than PAMAM G2. However, PAMAM G2-HRChol 6% and PAMAM G2-HRChol 23% dendrimers showed less buffering effect than did PAMAM G2-HR, presumably because of the decrease in the number of amine groups.
PH and redox dual-responsive polymeric micelles with charge conversion for paclitaxel delivery
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Bo Li, Shigang Pang, Xinxin Li, Yanhai Li
Amphiphilic dual-responsive polymers, mPEG-SS-PGA-IM, were synthesized as potential carriers of PTX for cancer therapy. mPEG-SS-PGA-IM formed nanoscale micelles in water and encapsulated PTX in hydrophobic inner core with relatively high loading efficiency. PTX-loaded mPEG-SS-PGA-IM micelles can release PTX at acidic condition and in the presence of GSH to mimic the reductive environment. Furthermore, mPEG-SS-PGA-IM micelles can escape from endo/lysosomes by the proton sponge effect. And PTX-loaded mPEG-SS-PGA-IM micelles exhibited higher cytotoxicity against HCT116 cells than PTX-loaded mPEG-SS-PBLG and mPEG-SS-PBLG micelles. There results suggest mPEG-SS-PGA-IM micelles have great potential as carriers of PTX and other hydrophobic drugs.
pH-responsive nanomicelles of poly(ethylene glycol)-poly(ε-caprolactone)-poly(L-histidine) for targeted drug delivery
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Penghui Wang, Wei Liu, Shuai Liu, Rong Yang, Yajie Pu, Wenjie Zhang, Xiaoxue Wang, Xin Liu, Yanhan Ren, Bo Chi
Confocal laser scanning microscope (CLSM) was used to observe the localization of free drug and drug-loaded micelles in MCF-7 cells, which were used to analyze the drug release pathway of drug-loaded micelles. Figure 7 shows that free DOX and DOX-loaded micelles were cultured for 1, 12, and 24 h respectively. It can be seen that the DOX content in cells increased significantly with the prolongation of culture time. When cultured for 1 and 12 h, we can see that the content of free DOX in cells was significantly higher than that of drug-loaded micelles, which indicated that drug-loaded micelles have excellent drug sustained release. After incubation for 1 h, it was obvious that the DOX-loaded micelles were highly coincident with the connotations. The results showed that the drug-loaded micelles were endocytosed by cancer cells and were absorbed into the intracellular inclusions. The fluorescence intensity increased after 12 h of culture, which further indicated that the concentration of DOX in cancer cells increased significantly. After 24 h of culture, compared with the free drug, we found that the DOX-loaded micelles basically coincided with the fluorescence in the nucleus, suggesting that the nucleus of MCF-7 cells ruptured and died. These results indicated that pH-sensitive PEG-PCL-PHis micelles can escape from lysosomes and transport anticancer drugs into the nucleus. This was due to the proton sponge effect of the protonation of PHis in the acidic environment of the endosomes or lysosomes, which led to the swelling of the endosomes and the rupture of the lysosome membrane, resulting in dox-loaded micelles escaping from the lysosomes and releasing drugs into the cytoplasm [47,48].