Table 2.
pH-responsive polymers for the modification of liposomes for drug delivery.
| Polymer | Responsive pH | Composition of Vesicles | Responsive Groups | Payload | TARGETING SITE | Properties | Ref. |
|---|---|---|---|---|---|---|---|
| Polymers/Modified Polymers | |||||||
| Octylamine-graft-poly (aspartic) (PASP-g-C8) | 5.0 | Lecithin/Chol/PASP-g-C8 (48:12:x, mass ratio) |
Carboxyl groups | Cytarabine (CYT) | Tumor cells | pH-induced destabilization of the liposomes, good biological stability, strong toxicity to tumor cells, and low effect on normal ones | [179] |
| Lipid-poly(2-ethylacrylic acid) (PEAA-C10) | 4.5 | PC/Chol/PEAA | Carboxyl group | Calcein | Potentially for tumor or localized infection | pH- and temperature-sensitive due to lipid-anchored PEAA and due to the introduction of diisopropylamide | [180] |
| MGlu-HA-C10, CHex-HA-C10 |
pKa = 5.37–6.70 | EYPC/HA derivatives | Carboxyl groups | Doxorubicin (DOX) |
Interior of cells | High molecular affinity to highly CD44-expressing cells and delivering drugs to the interior of cells as a result of pH-responsive membrane disruptive ability in endo/lysosomes | [181] |
| MGlu-HA and Chex-HA with anchor moieties (MGlu-HA-A14 and CHex-HA-A14) | - | EYPC/HA derivatives (7/3, w/w) | Carboxyl groups | A model antigenic protein ovalbumin (OVA) | Antigen-presenting cells (APCs), cytoplasm | Cytoplasmic delivery of OVA into dendritic cells, promoted Th1 cytokine production from these cells with CHex-HA-A | [182] |
| Succinylated poly(glycidol) (SucPG) |
- | EYPC/SucPG (9:1, 8:2, and 7:3, mass ratio) |
Carboxyl groups | Calcein | Cytoplasm | Transferring the content into cytoplasm by fusing with membranes of endosome and/or lysosome potentially with high stability and high efficiency | [183] |
| 3-methyl-glutarylated hyperbranched poly(glycidol)s (MGlu-HPGs-C10) | 6.5 | EYPC/polymer = 7/3, w/w | Carboxyl groups | Pyranine | Cytosol of DC2.4 cells | pH-sensitivity-inducing content release at mildly acidic pH, efficient drug-delivery to cytosol of DC2.4 cells | [184] |
| DSPE-PEG-H7K (R2)2 | 6.8 | DOPE/CHEMS/DSPE-PEG or DSPE-PEG-H7K (R2)2 | H7 sequence | DOX | Glioma | Tumor-specific pH-triggered DOX release under acidic conditions | [185] |
| DSPE-PEG2000-TH | ca. 6.5 (pKa of the imidazole ring) | Chol/SPC/DSPE-PEG2000 or DSPE-PEG2000-TH (33:59:2:6, molar ratio) | Imidazole ring in histidine | Paclitaxel (PTX) | Endoplasmic reticulum and Golgi apparatus, tumor cell | 86.3% tumor inhibition rate in mice | [186] |
| DSPE-PEG2000-STP | 5.8 | SPC/Chol/STP-PEG2000-DSPE/DOX (8:2:2:1, mass ratio) | -Lys-Asp-Glu-Glu-segment | DOX | Cytoplasm | Enhanced recognition ability and peneration by formation of α-helix at Lys-Asp-Glu-Glu-segment in the N-terminal in the presence of protons | [187] |
| R6H4-C18 | 6.4 | SPC/Chol (20:1, mass ratio), 2.5 mol% R6H4-C18 | Arginine and histidine | PTX | Tumor | Enhanced cellular uptake and intracellular drug delivery | [188] |
| pH-responsive block copolymer | |||||||
| Stearoyl-PEG- poly(methacryloyl sulfadimethoxine) copolymer (stearoyl-PEG-PSDM) |
7.0 | mPEG-DSPE/stearoyl-PEG-PSDM/lipid | Sulfadimethoxine | Cancer | Stable in serum, undergoing rearrangement in tumor-like environment, high intracellular drug delivery | [189] | |
| Poly(styrene-co-maleic acid) (PSMA) |
pK1: 5.27 | DSPC/SMA (20:1, molar ratio) | Carboxylate groups pK1: 5.27 |
Cytoplasmic delivery | Configurational transition of the polymer below pK1 leading to disruptive lipid bilayer of erythrocytes, enhanced cytosolic delivery of encapsulated biomolecules through endosome destabilization together with stability in serum, excellent cytocompatibility, and efficient drug delivery than unmodified liposomes | [190] | |
| Methoxy-poly(ethylene glycol)-b-poly(N-2-hydroxypropyl methacrylamide-co-histidine)-cholesterol [mPEG-P(HPMA-g-His)-Chol)] | 5.0 | mPEG-P(HPMA-g-His)-chol /DPPC (1:34, molar ratio) | Imidazole ring of histidine | DOX | Extracellular matrix (ECM) of tumor | ECM targeting, rapid drug release in an acidic environment, preferential tumor accumulation | [191] |
| PEGm-PDPAn-PEGm triblock copolymers | ca. 6.2 | HSPC or DOPC/Chol/PEGm-PDPAn-PEGm in various molar ratios | Tertiary amine groups | DOX | Tumor | pH-controllable drug release due to escape of the bola polymer from liposome at acidic pH as a result of hydrophobic to hydrophilic transition of the PDPA segment | [51] |
| C7H15-AZO-b-PDPAn-b-mPEG | 6.0 | HSPC/DOPC/Chol/C7H15-AZO-b-PDPAn-b-mPEG, with different ratios | Tertiary amine groups | DOX | - | pH- and photo-dual responsive | [192] |
| dePEGylation | |||||||
| mPEG-Hz-CHEMS | 5.5 [193] | Soy PC/Chol/ mPEG2000-Hz-CHEMS/PTX (90:10:3:3) | Hydrazone | - | - | Prolonged circulation time and almost eliminated ABC phenomenon | [194] |
| PEGB-Hz-DPPE | 5.0 | DOPE/DSPC/CHEMS/Chol/PEGB-Hz-DPPE (4:2:2:2:0.5, molar ratio) | Acid labile hydrazide–hydrazone hybrid bond | Calcein/gemcitabine | Tumor | Simultaneous long circulation and pH sensitivity, increased tumor aggregation | [195] |
| mPEG2000-Hz-stearate (PHS) |
<6.5 | SPC/cholesterol/PHS | Hydrazone bond | - | Tumor | Stronger pH sensitivity than that of PEG2000-Hz-PE, superior cellular uptake and endosomal escape | [196] |
| mPEG2000-Hz-Chol | 5.5 | S100PC/Chol/mPEG2000-Hz-Chol (90:10:3) | Hydrazone | PTX | Breast cancer cells | Highly sensitive to mild acidic environment, accumulative drug release and enhanced cellular uptake at pH 5.5 | [193] |
| PEG-diortho ester-distearoyl glycerol (POD) | 5.5 | POD/DOPE (1:9) | Diortho ester | ANTS and DPX | - | Stabilized liposome in serum and blood circulation, sensitive to acidic environment but stable in neutral pH | [197] |
MGlu-HA: 3-methylglutarylated hyaluronic acid; Chex-HA: 2-carboxycyclohexane-1-carboxylated hyaluronic acid; TH: an engineered a-helical cell penetrating peptide AGYLLGHINLHHLAHL(Aib)HHIL-NH2; PDPA: poly(2-(diisopropylamino) ethylmethacrylate; STP: a peptide SKDEEWHKNNFPLSP; ANTS: 8-aminonaphthalene-1,2,3-trisulfonic acid; DPX: p-xylenebis(pyridinium) bromide.