Poly(amidoamine)-mediated intracytoplasmic delivery of ricin A-chain and gelonin.
Poly(amidoamine)s (PAAs) are water-soluble synthetic polymers designed to be biodegradable and biocompatible. Moreover, they display membrane disruptive properties in response to a decrease in pH. This attribute confers PAAs with endosomolytic properties in vitro and in vivo. A model system was developed to quantify their ability to promote the endosomal escape of macromolecules that may be interesting as therapeutic agents. Here, two PAAs (ISA 1 and 4) were incubated with B16F10 cells in vitro together with two non-permeant toxins: either ricin A-chain (RTA) or gelonin. The relatively non-toxic PAAs ISA 1 and 4 (IC50>1.5 mg/ml) restored activity to the inherently inert toxins. The IC50 values for the ISA 1/RTA and ISA 1/gelonin combinations were 0.65+/-0.05 and 0.55+/-0.12 mg/ml, respectively. Similarly, when ISA 4 was incubated with a non-toxic combination of RTA and gelonin the IC50 value decreased to 0.57+/-0.03 and 0.43+/-0.26 mg/ml, respectively. In contrast, the neutral polymer dextran and the PAA ISA 22 were unable to mediate this effect. These observations suggest that specific PAA-toxin combinations warrant further development as novel therapeutics.
Pattrick
N G
NG
Centre for Polymer Therapeutics, Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, CF10 3XF, Cardiff, UK.
Richardson
S C
SC
Casolaro
M
M
Ferruti
P
P
Duncan
R
R
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009757:Nylons / Q000737:chemistry / Q000494:pharmacology; D010940:Plant Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D011073:Polyamines / Q000737:chemistry / Q000493:pharmacokinetics*; D011108:Polymers / Q000737:chemistry / Q000493:pharmacokinetics*; D054789:Ribosome Inactivating Proteins, Type 1; D012276:Ricin / Q000008:administration & dosage* / Q000737:chemistry; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D009757:Nylons; D010940:Plant Proteins; D011073:Polyamines; D011108:Polymers; D054789:Ribosome Inactivating Proteins, Type 1; C025674:GEL protein, Gelonium multiflorum; D012276:Ricin