Abstract
Cancer treatment by chemotherapy is typically accompanied by deleterious side effects, attributed to the toxic action of chemotherapeutics on proliferating cells from nontumor tissues. The cell surface proteoglycan CD44 has been recognized as a cancer stem cell marker. The present study has examined CD44 targeting as a way to selectively deliver therapeutic agents encapsulated inside colloidal delivery systems. CD44/chondroitin sulfate proteoglycan binds to a triple-helical sequence derived from type IV collagen, α1(IV)1263–1277. We have assembled a peptide-amphiphile (PA) in which α1(IV)1263–1277 was sandwiched between 4 repeats of Gly-Pro-4-hydroxyproline and conjugated to palmitic acid. The PA was incorporated into liposomes composed of DSPG, DSPC, cholesterol, and DSPE-PEG-2000 (1 : 4 : 5 : 0.5). Doxorubicin-(DOX-)loaded liposomes with and without 10% α1(IV)1263–1277 PA were found to exhibit similar stability profiles. Incubation of DOX-loaded targeted liposomes with metastatic melanoma M14#5 and M15#11 cells and BJ fibroblasts resulted in IC50 values of 9.8, 9.3, and >100 μM, respectively. Nontargeted liposomes were considerably less efficacious for M14#5 cells. In the CD44+ B16F10 mouse melanoma model, CD44-targeted liposomes reduced the tumor size to 60% of that of the untreated control, whereas nontargeted liposomes were ineffective. These results suggest that PA targeted liposomes may represent a new class of nanotechnology-based drug delivery systems.
Highlights
The ultimate goal of targeted nanotechnology-based drug delivery systems in cancer therapy is to improve the therapeutic index of cytotoxic agents by selectively increasing their concentration at the tumor site
In the current study we evaluated the stability of distearoyl phosphatidylglycerol-(DSPG-)distearoyl phosphatidylcholine (DSPC) DOX-loaded liposomes both with and without the α1(IV)1263–1277 PA
We have previously determined that liposomes composed of Distearoyl phosphatidylglycerol (DSPG), Distearoyl phosphatidylcholine (DSPC), and cholesterol form a stable liposomal delivery system [23, 62, 63]
Summary
The ultimate goal of targeted nanotechnology-based drug delivery systems (nanoDDSs) in cancer therapy is to improve the therapeutic index of cytotoxic agents by selectively increasing their concentration at the tumor site. Liposomes in particular have attracted much attention as site-specific drug delivery vehicles because of their biocompatibility [1, 2], and the ease with which they can be manipulated to accommodate targeting ligands to further increase the specificity and the potency of encapsulated chemotherapeutics [3]. CD44 has been revealed as a cancer stem cell marker for numerous tumor types [5, 11,12,13,14,15,16,17]. A theory is emerging that CD44 positive cells within a tumor display true stem cell properties
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