Nanoparticulate delivery system targeted to tumor neovasculature for combined anticancer and antiangiogenesis therapy.
OBJECTIVE
Herein, we designed a nanoparticulate combined delivery system decorated on the surface with RGD peptide, and encapsulating paclitaxel (PTX) and combretastatin A4 (CA4) as the respective anticancer and antiangiogenesis agent in the nanoparticle.


METHODS
PTX and CA4 were co-encapsulated into the biocompatible PLGA, followed by solvent evaporation to form solid nanoparticle. The cRGDfK peptide was then conjugated onto the nanoparticle surface with EDC/NHS chemistry.


RESULTS
The developed nanoparticles (NPs) were found uniform in size and well dispersed in buffers. The cellular uptake of such NPs could be efficiently detected as early as 20 min after incubation. In 24-h incubation, the encapsulated PTX could induce caspase 3/7-dependent apoptosis at 50 nM, whereas the CA4-loaded NPs could disrupt tubulin structure at 2.5 μM. The targeted dual drug-loaded nanoparticle achieved significant tumor growth suppression in vivo compared to the control from day 8 (P < 0.05). Histological results revealed that the targeted dual drug nanoparticle led to dramatic tumor vasculature disruption, significant cancer cell apoptosis and cell proliferation inhibition in the mouse model.


CONCLUSIONS
These findings indicate that the targeted dual drug nanoparticulate delivery system encompassing both antiangiogenesis and anticancer effects can be a potential candidate in cancer therapy.
Laboratory for Experimental and Applied Pharmacokinetics and Pharmacodynamics, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
Zhe
Z
Wang
Wai-Keung
WK
Chui
Paul C
PC
Ho
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016503:Drug Delivery Systems / Q000379:methods*; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D020533:Angiogenesis Inhibitors; D000972:Antineoplastic Agents, Phytogenic