A Virus-Mimicking, Endosomolytic Liposomal System for Efficient, pH-Triggered Intracellular Drug Delivery

Abstract

A novel multifunctional liposomal delivery platform has been developed to resemble the structural and functional traits of an influenza virus. Novel pseudo-peptides were prepared to mimic the pHresponsive endosomolytic behavior of influenza viral peptides through grafting a hydrophobic amino acid, L-phenylalanine, onto the backbone of a polyamide, poly(L-lysine isophthalamide), at various degrees of substitution. These pseudo-peptidic polymers were employed to functionalize the surface of cholesterol-containing liposomes that mimic the viral envelope. By controlling the cholesterol proportion, as well as the concentration and amphiphilicity of the pseudo-peptides, the entire payload was rapidly released at endosomal pHs whilst there was no release at pH 7.4. A pH-triggered, reversible change in liposomal size was observed and the release mechanism was elucidated. In addition, the virus-mimicking nanostructures efficiently disrupted the erythrocyte membrane at pH 6.5 characteristic of early endosomes, whilst showed negligible cytotoxic effects at physiological pH. The efficient intracellular delivery of the widely used anticancer drug doxorubicin (DOX) by the multifunctional liposomes was demonstrated, leading to significantly increased potency against HeLa cancer cells over the DOX-loaded bare liposomes. This novel virus-mimicking liposomal system, with the incorporated synergy of efficient liposomal drug release and efficient endosomal escape, is favorable for efficient intracellular drug delivery.3

An activated-platelet-sensitive nanocarrier enables targeted delivery of tissue plasminogen activator for effective thrombolytic therapy

“…First, passive tPA release from the liposomal formulations in pH 7.4 PBS buffer at 37 o C was examined. As shown inFigure S7, percentages of tPA released from tPA-lip, tPA-PEG-lip and tPA-PEG-cRGD-lip were all around 10% after 6 h. This indicates that the liposomal formulations containing 40 mol% cholesterol could effectively retain tPA with relatively low passive drug release[48]. This is necessary for the entrapped tPA to survive in the blood circulation and then accumulate to activated platelets of a thrombus.…”

“…tPA-loaded liposome without surface modification, tPA-lip, and the tPA-loaded liposome surface modified by PEG only, tPA-PEG-lip, were prepared for comparison ( Figure 1A). The molar percentage of cholesterol at 40 mol% was chosen to prepare liposome formulations with desirable stability and minimal drug leakage according to our previous work [48]. Liposomal formulations were characterized for their particle size, morphology, PDI, zeta potential and encapsulation efficiency.…”

Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular Delivery

“…[5][6][7][8] Particular interest has been focused on development of anionic polymers as drug carriers to mimic the pH-dependent membrane disruptive behavior of fusogenic viral peptides. [9][10][11] The polyanions containing both hydrophobic segments and weakly ionizable carboxyl groups can exhibit more favorable biodistribution and significantly lower cytotoxicity compared to polycations. 12 As pH decreases below their pKa, they display a coil-to-globule conformational change due to the protonation of carboxylate ions, which, as a result, leads to lipid membrane destabilization.…”

Virus‐mimetic systems for cancer diagnosis and therapy

“…Since the first liposome‐based nanomedicine Doxil approved by the FDA in 1995, liposomes have been proven to be one of the most promising nonviral carriers (Barenholz, 2012). S. Chen and Chen (2016) reported a multifunctional liposome delivery platform. The liposomal structure mimics the envelope of the virus, and the encapsulated doxorubicin mimics the viral genome.…”