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A detachable coating of cholesterol-anchored PEG improves tumor targeting of cell-penetrating peptide-modified liposomes.

Tang J, Zhang L, Fu H, Kuang Q, Gao H, Zhang Z, He Q - Acta Pharm Sin B (2014)

Bottom Line: Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo.With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs.The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

ABSTRACT
Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo. In this study, cholesterol-anchored, reduction-sensitive PEG (first synthesized by our laboratory) was applied to develop a co-modified liposome with improved tumor targeting. Following optimization of the formulation, the in vitro and in vivo properties of the co-modified liposome were evaluated. The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake, but a much higher tumor accumulation compared to CPP-modified liposome, indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating. With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs. The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.

No MeSH data available.


Related in: MedlinePlus

Representative CLSM images of C26 tumor spheroids incubated with different CFPE-labeled liposomes at 37 °C for 4 h.
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f0020: Representative CLSM images of C26 tumor spheroids incubated with different CFPE-labeled liposomes at 37 °C for 4 h.

Mentions: The three-dimensional tumor spheroid models are commonly used as an ideal in vitro platform mimicking solid tumors to predict delivery efficiency and mechanism22. To further evaluate the delivery characteristics of liposomes, tumor spheroid uptake experiments were carried out. At 4 h, little fluorescence was detected within tumor spheroids from PEG-LP and CL-R8-LP (in the absence of Cys). In contrast, R8-LP and CL-R8-LP (in the presence of Cys) treated tumor spheroids demonstrated much greater fluorescence (Fig. 4), indicating that the modification and exposure of R8 on the liposomal surface could not only increase the uptake by C26 cells but also facilitate the delivery of liposomes into tumor spheroids.


A detachable coating of cholesterol-anchored PEG improves tumor targeting of cell-penetrating peptide-modified liposomes.

Tang J, Zhang L, Fu H, Kuang Q, Gao H, Zhang Z, He Q - Acta Pharm Sin B (2014)

Representative CLSM images of C26 tumor spheroids incubated with different CFPE-labeled liposomes at 37 °C for 4 h.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4590295&req=5

f0020: Representative CLSM images of C26 tumor spheroids incubated with different CFPE-labeled liposomes at 37 °C for 4 h.
Mentions: The three-dimensional tumor spheroid models are commonly used as an ideal in vitro platform mimicking solid tumors to predict delivery efficiency and mechanism22. To further evaluate the delivery characteristics of liposomes, tumor spheroid uptake experiments were carried out. At 4 h, little fluorescence was detected within tumor spheroids from PEG-LP and CL-R8-LP (in the absence of Cys). In contrast, R8-LP and CL-R8-LP (in the presence of Cys) treated tumor spheroids demonstrated much greater fluorescence (Fig. 4), indicating that the modification and exposure of R8 on the liposomal surface could not only increase the uptake by C26 cells but also facilitate the delivery of liposomes into tumor spheroids.

Bottom Line: Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo.With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs.The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

ABSTRACT
Cell-penetrating peptides (CPPs) have been widely used to enhance the membrane translocation of various carriers for many years, but the non-specificity of CPPs seriously limits their utility in vivo. In this study, cholesterol-anchored, reduction-sensitive PEG (first synthesized by our laboratory) was applied to develop a co-modified liposome with improved tumor targeting. Following optimization of the formulation, the in vitro and in vivo properties of the co-modified liposome were evaluated. The co-modified liposome had a much lower cellular uptake and tumor spheroid uptake, but a much higher tumor accumulation compared to CPP-modified liposome, indicating the non-specific penetration of CPPs could be attenuated by the outer PEG coating. With the addition of exogenous reducing agent, both the in vitro and in vivo cellular uptake was markedly increased, demonstrating that the reduction-sensitive PEG coating achieved a controllable detachment from the surface of liposomes and did not affect the penetrating abilities of CPPs. The present results demonstrate that the combination of cholestervsitive PEG and CPPs is an ideal alternative for the application of CPP-modified carriers in vivo.

No MeSH data available.


Related in: MedlinePlus