Poly(styrene-co-maleic acid)-based pH-sensitive liposomes mediate cytosolic delivery of drugs for enhanced cancer chemotherapy

• Published in: International journal of pharmaceutics 2012-10, Vol.436 (1-2), p.786-797
• Main Authors: Banerjee, Shubhadeep, Sen, Kacoli, Pal, Tapan K., Guha, Sujoy K.
• Format: Article
• Language: English
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - chemistry; Apoptosis; blood serum; Cell Cycle - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Cells, Cultured; chemotherapy; colorectal neoplasms; composite polymers; Cytocompatible; Cytosol - metabolism; drugs; encapsulation; endosomes; erythrocytes; Erythrocytes - drug effects; Erythrocytes - physiology; Erythrocytes - ultrastructure; Fluorouracil - administration & dosage; Fluorouracil - chemistry; hemolysis; Hemolysis - drug effects; HT29 Cells; Humans; Hydrogen-Ion Concentration; Liposomes; Male; Maleates - administration & dosage; Maleates - chemistry; Mice; NIH 3T3 Cells; pH-sensitive; Phosphatidylcholines - administration & dosage; Phosphatidylcholines - chemistry; Poly(styrene-co-maleic acid); Polystyrenes - administration & dosage; Polystyrenes - chemistry
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2012.07.059

pH-induced alterations in SMA conformation causes the co-polymer-based liposomes to fuse with endosomes and mediate cytosolic delivery of encapsulated drugs which ultimately leads to enhanced chemotherapy. pH-responsive polymers render liposomes pH-sensitive and facilitate the intracellular release of encapsulated payload by fusing with endovascular membranes under mildly acidic conditions found inside cellular endosomes. The present study reports the use of high-molecular weight poly(styrene-co-maleic acid) (SMA), which exhibits conformational transition from a charged extended structure to an uncharged globule below its pK1 value, to confer pH-sensitive property to liposomes. The changes in the co-polymer chain conformation resulted in destabilization of the liposomes at mildly acidic pH due to vesicle fusion and/or channel formation within the membrane bilayer, and ultimately led to the release of the encapsulated cargo. The vesicles preserved their pH-sensitivity and stability in serum unlike other polymer-based liposomes and exhibited no hemolytic activity at physiological pH. The lysis of RBCs at endosomal pH due to SMA-based liposome-induced alterations in the bilayer organization leading to spherocyte formation indicated the potential of these vesicles to mediate cytosolic delivery of bio-active molecules through endosome destabilization. The SMA-loaded liposomes exhibiting excellent cytocompatibility, efficiently delivered chemotherapeutic agent 5-Fluorouracil (5-FU) within colon cancer cells HT-29 in comparison to neat liposomes. This caused increased cellular-availability of the drug, which resulted in enhanced apoptosis and highlighted the clinical potential of SMA-based vesicles.