Novel pH responsive vesicles for siRNA delivery to the tumor

“Smart” polymers with adequate properties can be assembled into responsive carriers that can be exploited to improve the site selective drug delivery to target tissues. In this work two triblock pH-responsive co-polymers were synthesized to be assembled in vesicles for the delivery of siRNA to cancer cells. The conjugation of folic acid on the carrier surface will allow targeting the folate receptor overexpressed by many cancer tissues. The vesicles forming polymers were synthesized in order to respond to the acid environment of the endosomal compartment with prompt disassembly of the nanocarrier and siRNA release. Appropriate siRNA sequence have been chosen to silence the expression of the α1 subunit of the Na+/K+ ATPase that is often involved in the hyper-proliferation of lung cancer cells. The triblock copolymers include two hydrophilic blocks at the terminal ends, namely PEG2kDa or 3.5kDa and poly-glycerolmethacrylate; and a central pH sensitive portion, poly-C6-imidazoyl methacrylate. The polymer bearing PEG 3.5kDa is intended to be conjugated with the targeting agent folic acid. The vesicles are prepared by mixing the two polymers at different ratios. The copolymers self-assemble in vesicles at pH 7.4 with a size of 76.7 ± 1.6 nm and are very stable at room temperature. At 37°C the stability of the vesicles can be modulated by increasing the ratio of the copolymer with PEG 3.5kDa. The vesicles were imaged by TEM microscopy showing a spherical shape and high size homogeneity. The carrier loads very efficiently double stranded DNA sequences with a 14% molar loading yield and release them in 6 hours when incubated at pH 5 while vesicles showed negligible DNA release at pH 7.4.