Tumor cell endosomes, release

Fig. 2 Schematic demonstration of different routes of drug release and cellular uptake. After a drug delivery system is administered, different events occur. Route a drug A is released during circulation and is taken up by both normal cells and tumor cells. Route b drug B is transported to the tumor interstitum and released extracellularly at the tumor site, and mainly taken up by tumor cells. Route c drug C is endocytosed with its carrier and released in the endosomes or lysosomes.

Fig. 5 Schematic diagram of the siRNA delivery system. A cationic group is universal in all siRNA delivery systems to condense siRNA into nanosized complex. To release the siRNA from the endosome after endocytosis, an endosomal disrupting agent is also essential. PEG modification is also important to improve the pharmacokinetic profile of the complex, as well as to avoid the nonspecific uptake by RES. To achieve the targeted delivery to tumor cells, various ligands including antibody, antibody fragments, peptides, small molecules should be modified to the complex directly or via PEG as a linker...

Pirollo et al. developed a nanoimmunoliposome modified with anti-TfR scFV to deliver siRNA to tumor cells. A fluorescein-labeled siRNA was delivered via systemic injection and it was specifically distributed into primary and metastatic tumor cells [110]. Later, the authors developed a similar nanoimmunoliposome for an anti-Her-2 siRNA. To enhance the endosomal release, a pH-sensitive histidine-lysine peptide was included in the complex. The in vitro results showed that the complexes can sensitize human cancer cells to che-motherapeutics. Furthermore, systemic delivery of the siRNA significantly inhibit tumor growth in a pancreatic cancer model [109]. 

Nano-sized polymers and particles adhere on the surface of tumor cells, and are taken up into tumor cells by endocytosis or macropinocytosis. In the endocytic pathway, pH gradually decreases from 7.4 (physiological pH) to 6 (endosomal pH) and to 5 (lysosomal pH). Eor intracellular release of pDNA, poly[Asp(Hyd-PEG)]-block-p[Asp(diaminoethane)] (Eigure 10.1(b)) has been reported to show high... 

The in vitro release profiles of DOX from the polymeric micelles was studied in in PBS (0.1 M, pH 7.4) and acetate buffer solutions (0.1 M, pH 5.4) at 37 °C. The results showed an initial burst release of DOX and followed by a sustained release for about 48 h. The initial burst release of DOX from micelles could be attributed to the diffusion of DOX located close to the surface of particles or within the hydrophilic shell [6]. The total release of DOX in a period of 48 h with pH 7.4 and 5.4 was 25% and 37% of total DOX concentration, respectively. However, the release of DOX at a pH value of 5.4 was found faster than that at a pH value of 7.4. These results could be attributed to the re-protonation of the amino group of DOX and the faster degradation of the micelle core at lower pH values. This pH-dependent release profile is of particular interest. It is expected that the greater part of DOX-loaded micelles will remain in the micelles cores for a considerable time period in plasma after intravenous administration and have the potential for prolonged DOX retention time in the blood circulatioa However, a faster release may occur at low local pH surrounding the tumor site or by the more acidic environment inside the endosome and lysosome of tumor cells after cellular uptake of micelles through endocytosis. 

MCF-7 cells and their xenograph tumors, and compared with DOX-loaded pH-insensitive micelles made of PLLA-PEG with folate targeting groups (PHlM/f) [99]. The cellular localization of the nanoparticles was confirmed by confocal microscopy (Fig. 10.13). DOX delivered by PHSM/f was found uniformly distributed in the cytosol as well as in the nucleus, while DOX/PHlM/f was entrapped in endosome and multivesicular bodies. It was thus hypothesized that PHis, which is known to have an endosomal membrane-disruption activity induced by a proton sponge mechanism of its imidazole groups [209, 210], disrupted the compartment membrane and released DOX into the cytosol. As a result, DOX/PHSM/f showed much higher in vitro and in vivo anticancer activities toward DOX-resistant cells (Fig. 10.14). 

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