Stimuli-responsive liposomes for drug delivery

Abstract

The ultimate goal of drug delivery is to increase the bioavailability and reduce the toxic side effects of the active pharmaceutical ingredient (API) by releasing them at a specific site of action. In the case of antitumor therapy, association of the therapeutic agent with a carrier system can minimize damage to healthy, nontarget tissues, while limit systemic release and promoting long circulation to enhance uptake at the cancerous site due to the enhanced permeation and retention effect (EPR). Stimuli-responsive systems have become a promising way to deliver and release payloads in a site-selective manner. Potential carrier systems have been derived from a wide variety of materials, including inorganic nanoparticles, lipids, and polymers that have been imbued with stimuli-sensitive properties to accomplish triggered release based on an environmental cue. The unique features in the tumor microenvironment can serve as an endogenous stimulus (pH, redox potential, or unique enzymatic activity) or the locus of an applied external stimulus (heat or light) to trigger the controlled release of API. In liposomal carrier systems triggered release is generally based on the principle of membrane destabilization from local defects within bilayer membranes to effect release of liposome-entrapped drugs. This review focuses on the literature appearing between November 2008-February 2016 that reports new developments in stimuli-sensitive liposomal drug delivery strategies using pH change, enzyme transformation, redox reactions, and photochemical mechanisms of activation. WIREs Nanomed Nanobiotechnol 2017, 9:e1450. doi: 10.1002/wnan.1450 For further resources related to this article, please visit the WIREs website.

Fig. 1

Schematic diagram of a liposome comprised of a spherical phospholipid lipid bilayer.

Fig. 2

Enhanced permeability and retention (EPR) effect. The vasculature in the tumor environment is poorly formed, enabling nanocarriers to enter the surrounding tumor tissue passively through “leaky” endothelial cell junctions.

Fig. 3

Different liposomal designs for targeted drug delivery. Drugs can be incorporated within the aqueous core or bilayer membrane depending on the drug properties. The degree of PEGylation (the dimensions shown are for PEG2000) can be adjusted to vary the stealth characteristics of the liposome formulation. Ligands can be introduced to present on the surface to manage specific binding while drug release rate can be controlled by designing in sensitivity to specific stimuli.

Fig. 4

Liposome permeability changes that can occur upon intracellular activation of liposome membrane destabilization or membrane-membrane fusion. Similarly, extracellular activation can also increase membrane permeability to release drug cargo in the cell microenvironment.

Fig. 5

Gadolinium-based complexes release from the fusogenic liposomes upon acidification to enhance the relaxivity for better visualization.

Fig. 6

Change in the chemical structures of the model polymers at acidic pH via protonation.

Fig. 7

Chemical structure of (a) 3-methylglutarylated poly(glycidol) (MGlu-HG) and (b) 3,5-Didodecyloxybenzamidine (TRX).

Fig. 8

The neutral malachite green carbiniol base (MG) becomes into carbocation state (MG⁺) upon acidification which causes membrane destabilization and contents release.

Fig. 9

Pseudomonas aeruginosa dirhamnolipids (diRL) contain a carboxylate group that is negatively charged at neutral pH, but neutral at acidic pH.

Fig. 10

Multistage pH-responsive mechanisms based on (a) HHG2C₁₈ and (b) PEGHG2C₁₈.

Fig. 11

Chemical structure of (a) β-CD and (b) anthraquinone derivative. (c) Supramolecular amphiphile consists of hydrophilic head and hydrophobic tail groups that undergo a pH-dependent, reversible complexation.

Fig. 12

(a) Protonation-induced conformational switch of lipid tails in an amphiphile. (b) Protonation-induced conformational flip, shortening of the lipid tails causes rapid perturbation of the lipid bilayer, lipid phase separation, and fast release from the fliposomes.

Fig. 13

Acid-catalyzed hydrolysis of the cationic ortho ester lipids.

Fig. 14

Schematic representation of an acid-degradable siRNA-loaded polymer-caged lipoplex (PCL) and its releasing mechanism.

Fig. 15

Acid-catalyzed vinyl ether hydrolysis mechanism involving a protonation of the β-carbon in a rate-determining step (r.d.s.).

Fig. 16

Hydrazone bond hydrolysis mechanism

Fig. 17

Reversible reactions of oxime formation at pH 4.0 and oxime hydrolysis at pH 5.5.

Fig. 18

Enzyme-mediated intramolecular cyclization to release the lipid-based prodrug of capsaicin.

Fig. 19

Mechanism of catalytic Zn(II)-mediated peptide link hydrolysis involving Ala192 and Glu404.

Fig. 20

Structure of the copolymer NIPAM/MAA/ODA (mass ratio of x: NIPAM, y: MAA, z: ODA).

Fig. 21

Conversion of glucose to gluconic acid in the presence of glucose oxidase.

Fig. 22

Glutathione reductase (GR) induces the conversion of GSSG to GSH that facilitates the release of encapsulated peptide due to the cleavage of the disulfide bond linking the polymer carrier (PMA) and the peptide (KP9).

Fig. 23

General structure of (a) bolaamphiphilic compound (b) choline ester headgroup (c) symmetric bolaamphiphilic compound (d) asymmetric bolaamphiphilic compound.

Fig. 24

Generalized mechanism for AChE hydrolysis of acetylcholine.

Fig. 25

Schematic representation of dithiothreitol (DTT)-induced disruption of disulfide bonds through reduction.

Fig. 26

Chemical structure of SS14.

Fig. 27

Chemical structures of disulfide- and ketal-containing cleavable linkers.

Fig. 28

Chemical mechanism of reduction and intramolecular cyclization of Quinone Propionic Acid (QPA) trigger group to trigger the cleavage of linker.

Fig. 29

Chemical structure of bis(11-ferrocenylundecyl)dimethylammonium bromide (BFDMA) and reversible redox mechanism.

Fig. 30

Schematic reactions of (a) photo-induced cis-trans conformational changes, (b) photocleavage of lipids upon exposure to light-mediated formation of ROS, and (c) photopolymerization of lipids containing double or triple bonds.

Fig. 31

General mechanisms of photooxidation. (a) Type I: electron transfer reaction catalyzing the formation of radical species. Type II: energy transfer reaction catalyzing the formation of singlet oxygen. Photosensitizer (PS): ground state, ¹PS: singlet, ³PS: triplet states. Oxygen (O₂): ground state, ¹O₂: singlet excited state. (b) Formation of lipid hydroperoxide by ene reaction between the lipid double bond and singlet oxygen.

Fig. 32

Schematic representation of the DOX-loaded gold nanoshell (DOX-loaded liposome/SiO₂/Au) formation. Silica shell formed through the hydrolyzation of TEOS then coated with Au shell through the reaction of Au chloride tetrahydrate and hydroxylamine. TEOS: tetraethyl orthosilicate.