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Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy

Mohanty, Ayeskanta, Uthaman, Saji, Park, In-Kyu·2020·Molecules
DOI 10.3390/molecules25194377PMC PMC7582728
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Abstract

Cancer represents one of the most dangerous diseases, with 1.8 million deaths worldwide. Despite remarkable advances in conventional therapies, these treatments are not effective to completely eradicate cancer. Nanotechnology offers potential cancer treatment based on formulations of several nanoparticles (NPs). Liposomes and polymeric nanoparticle are the most investigated and effective drug delivery systems (DDS) for cancer treatment. Liposomes represent potential DDS due to their distinct properties, including high-drug entrapment efficacy, biocompatibility, low cost, and scalability. However, their use is restricted by susceptibility to lipid peroxidation, instability, burst release of drugs, and the limited surface modification. Similarly, polymeric nanoparticles show several chemical modifications with polymers, good stability, and controlled release, but their drawbacks for biological applications include limited drug loading, polymer toxicity, and difficulties in scaling up. Therefore, polymeric nanoparticles and liposomes are combined to form polymer-lipid hybrid nanoparticles (PLHNPs), with the positive attributes of both components such as high biocompatibility and stability, improved drug payload, controlled drug release, longer circulation time, and superior in vivo efficacy. In this review, we have focused on the prominent strategies used to develop tumor targeting PLHNPs and discuss their advantages and unique properties contributing to an ideal DDS.

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Figure 1 Overall schematic representation of polymer-lipid hybrid nanoparticles (PLHNPs) and their applications. The hybrid system is developed from polymeric nanoparticles and liposomes covered by different types of PLHNPs. (A) Polymer core lipid shell, (B) Polymer caged liposome, (C) Monolithic PLHNPs, (D) Erythrocyte membrane-coated PLHNPs), (E) Core shell-type hollow lipid-polymer-lipid hybrid nanoparticles. The different applications of PLHNPs are also shown. (1) Delivery of various chemotherapeutic drugs. (2) Delivery of genes (siRNA, DNA). (3) Delivery of vaccines, ovalbumin (OVA), and Toll-Like Receptor (TLR) agonist for immune activation. (4) Imaging applications based on gadolinium (Gd), manganese (Mn), and gold (Au). (5) Photothermal therapy (PTT), photodynamic therapy (PDT), ultrasound, and alternative magnetic field (AMF).
Figure 1 Overall schematic representation of polymer-lipid hybrid nanoparticles (PLHNPs) and their applications. The hybrid system is developed from polymeric nanoparticles and liposomes covered by different types of PLHNPs. (A) Polymer core lipid shell, (B) Polymer caged liposome, (C) Monolithic PLHNPs, (D) Erythrocyte membrane-coated PLHNPs), (E) Core shell-type hollow lipid-polymer-lipid hybrid nanoparticles. The different applications of PLHNPs are also shown. (1) Delivery of various chemotherapeutic drugs. (2) Delivery of genes (siRNA, DNA). (3) Delivery of vaccines, ovalbumin (OVA), and Toll-Like Receptor (TLR) agonist for immune activation. (4) Imaging applications based on gadolinium (Gd), manganese (Mn), and gold (Au). (5) Photothermal therapy (PTT), photodynamic therapy (PDT), ultrasound, and alternative magnetic field (AMF).CC BY · PubMed Central
Figure 2 Synthesis of polymer-lipid hybrid nanoparticles. (A) One-step synthesis of PLHNPs by mixing drug-containing polymeric solution and aqueous lipid solutions. (B) Two-step synthesis of PLHNPs by mixing liposomes with the prepared polymeric drug solutions.
Figure 2 Synthesis of polymer-lipid hybrid nanoparticles. (A) One-step synthesis of PLHNPs by mixing drug-containing polymeric solution and aqueous lipid solutions. (B) Two-step synthesis of PLHNPs by mixing liposomes with the prepared polymeric drug solutions.CC BY · PubMed Central
Figure 3 Schematic representation of advantages of different PLHNPs. (A) Polyethylene glycol (PEG)-lipid functionalization of PLHNPs prolongs the systemic circulation in the reticuloendothelial system (RES), inhibition of phagocytic uptake, and polymer tailing for the functionalization of targeting ligands. (B) The cationic lipid/polymer functionalization enhances the delivery of any drug, gene, vaccine, or imaging agent into the cells, resulting in theranostics applications against cancer. (C) A variety of PLHNPs facilitate multidrug encapsulation with drug release induced by different polymers and lipids, passive targeting by PEG polymer, and advanced therapeutic effectiveness of the hybrid system. (D) The surface fictionalizations of different target ligands enhance the cellular uptake and therapeutic efficacy as well as site-specific drug delivery. (E) The cell membrane coating of PLHNPs provides a natural homotypic targeting with extended circulation by simulating the membrane and inhibiting the phagocytic uptake by immune cells.
Figure 3 Schematic representation of advantages of different PLHNPs. (A) Polyethylene glycol (PEG)-lipid functionalization of PLHNPs prolongs the systemic circulation in the reticuloendothelial system (RES), inhibition of phagocytic uptake, and polymer tailing for the functionalization of targeting ligands. (B) The cationic lipid/polymer functionalization enhances the delivery of any drug, gene, vaccine, or imaging agent into the cells, resulting in theranostics applications against cancer. (C) A variety of PLHNPs facilitate multidrug encapsulation with drug release induced by different polymers and lipids, passive targeting by PEG polymer, and advanced therapeutic effectiveness of the hybrid system. (D) The surface fictionalizations of different target ligands enhance the cellular uptake and therapeutic efficacy as well as site-specific drug delivery. (E) The cell membrane coating of PLHNPs provides a natural homotypic targeting with extended circulation by simulating the membrane and inhibiting the phagocytic uptake by immune cells.CC BY · PubMed Central
Figure 4 Different types of polymer-lipid hybrid nanoparticles and their structural advantages. (A) Polymer core lipid shell. (B) Core shell-type hollow lipid-polymer-lipid hybrid nanoparticles. (C) Monolithic PLHNPs. (D) Polymer-caged liposome. (E) Erythrocyte membrane coated PLHNPs.
Figure 4 Different types of polymer-lipid hybrid nanoparticles and their structural advantages. (A) Polymer core lipid shell. (B) Core shell-type hollow lipid-polymer-lipid hybrid nanoparticles. (C) Monolithic PLHNPs. (D) Polymer-caged liposome. (E) Erythrocyte membrane coated PLHNPs.CC BY · PubMed Central
Figure 5 Synthesis of Cholesterol-PEG-SS-Transferrin and the transmission electron microscopy (TEM) image of afatinib-loaded cho-PEG-ss-Tf PLHNPs. The particle was synthesized by conjugating cholesterol-PEG and transferrin with cysteamine via amide bond formation, followed by afatinib (a tyrokinase inhibitor) loaded into the PLGA core through hydrophobic interactions. Transferrin protein binds to the transferrin receptor at the cell membrane and enhances drug delivery in the tumor cells and resulted in glutathione (GSH) stimuli responsive (disulphide bond breakage in the presence of GSH) drug release. Reprinted with permission from [86], Copyright © 2019 under American Chemical Society.
Figure 5 Synthesis of Cholesterol-PEG-SS-Transferrin and the transmission electron microscopy (TEM) image of afatinib-loaded cho-PEG-ss-Tf PLHNPs. The particle was synthesized by conjugating cholesterol-PEG and transferrin with cysteamine via amide bond formation, followed by afatinib (a tyrokinase inhibitor) loaded into the PLGA core through hydrophobic interactions. Transferrin protein binds to the transferrin receptor at the cell membrane and enhances drug delivery in the tumor cells and resulted in glutathione (GSH) stimuli responsive (disulphide bond breakage in the presence of GSH) drug release. Reprinted with permission from [86], Copyright © 2019 under American Chemical Society.CC BY · PubMed Central
Figure 6 Synthesis of multifunctional LTSL (Lysolipid-containing thermosensitive liposomes) targeting CD44 receptor. The hyaluronic acid-paclitaxel (HA-PTX)-self-assembled, conjugated thermosensitive liposomes carried a large payload of marimastat (MATT) in the lipid shell with efficient MMP enzymatic inhibition of lung metastasis. Reprinted with permission from [91], Copyright © 2018 under American Chemical Society.
Figure 6 Synthesis of multifunctional LTSL (Lysolipid-containing thermosensitive liposomes) targeting CD44 receptor. The hyaluronic acid-paclitaxel (HA-PTX)-self-assembled, conjugated thermosensitive liposomes carried a large payload of marimastat (MATT) in the lipid shell with efficient MMP enzymatic inhibition of lung metastasis. Reprinted with permission from [91], Copyright © 2018 under American Chemical Society.CC BY · PubMed Central
Figure 7 Dual targeted intelligent PLHNPs. The antibody-attached and SnMP (inhibitor)-loaded hybrid system exhibit a synergistic effect of chemo-sensitization and immune activation through hemeoxygenase-1 (HO-1) inhibition in acute myelogenous leukaemia cells. Reproduced with copyright permission from [107], under Creative Common Attribution 4.0 International License (CC.BY license).
Figure 7 Dual targeted intelligent PLHNPs. The antibody-attached and SnMP (inhibitor)-loaded hybrid system exhibit a synergistic effect of chemo-sensitization and immune activation through hemeoxygenase-1 (HO-1) inhibition in acute myelogenous leukaemia cells. Reproduced with copyright permission from [107], under Creative Common Attribution 4.0 International License (CC.BY license).CC BY · PubMed Central
Figure 8 (1) Synthesis of drug delivery system (DDS) based on redox-responsive polymer-lipid-peptide hybrid NPs based to deplete tumor against lung carcinoma. (2A) The hybrid system is loaded with cisplatin and paclitaxel, which results in a synergistic effect of the chemotherapeutic agent treatment with high cellular uptake in the lung cancer, data represent mean ±SD (n = 6), * p < 0.05, and (2B) Fluorescence images resulted RGD-modified LPHNPs exhibit stronger fluorescence than non-ligand modified hybrid NPs. Reprinted with permission from [111], Copyright © 2018 Elsevier Masson SAS.
Figure 8 (1) Synthesis of drug delivery system (DDS) based on redox-responsive polymer-lipid-peptide hybrid NPs based to deplete tumor against lung carcinoma. (2A) The hybrid system is loaded with cisplatin and paclitaxel, which results in a synergistic effect of the chemotherapeutic agent treatment with high cellular uptake in the lung cancer, data represent mean ±SD (n = 6), * p < 0.05, and (2B) Fluorescence images resulted RGD-modified LPHNPs exhibit stronger fluorescence than non-ligand modified hybrid NPs. Reprinted with permission from [111], Copyright © 2018 Elsevier Masson SAS.CC BY · PubMed Central
Figure 9 The synthesis of CD133 aptamer-conjugated all-trans-retinoic acid (ATRA) carrying PLHNPs. Reproduced with permission from [116], under Creative Common Attribution 4.0 International License (CC.BY license).
Figure 9 The synthesis of CD133 aptamer-conjugated all-trans-retinoic acid (ATRA) carrying PLHNPs. Reproduced with permission from [116], under Creative Common Attribution 4.0 International License (CC.BY license).CC BY · PubMed Central
Figure 10 A hybrid polymer-lipid shell representing the targeted GSH-sensitive, ultrasound-triggered DDS. The hybrid system comprises a perfluorohexane (PFH) liquid core and platinum prodrug inside the lipid layer. The hybrid DDS often emits echogenic signals and enhanced therapeutic treatment via increased reactive oxygen species (ROS) level. Reproduced with the permission from [58] under Creative Commons Attribution 4.0 International License (CC.BY-NC license).
Figure 10 A hybrid polymer-lipid shell representing the targeted GSH-sensitive, ultrasound-triggered DDS. The hybrid system comprises a perfluorohexane (PFH) liquid core and platinum prodrug inside the lipid layer. The hybrid DDS often emits echogenic signals and enhanced therapeutic treatment via increased reactive oxygen species (ROS) level. Reproduced with the permission from [58] under Creative Commons Attribution 4.0 International License (CC.BY-NC license).CC BY · PubMed Central
Figure 11 Synthesis of CSLPHNPs for delivery of siRNA with enhanced in vivo stability. The hybrid system synthesized by three-staged microfluidic technology with polyethyleneimine-polycaprolactone (PEI-PCL) in organic phase further coated over gene-loaded neutral lipid layer. Due to the lipid membrane coating, the core-shell contains reversed micelle via hydrophobic interaction, resulting in enhanced stability in vivo. Reprinted with permission from [136], Copyright © 2020, American Chemical Society.
Figure 11 Synthesis of CSLPHNPs for delivery of siRNA with enhanced in vivo stability. The hybrid system synthesized by three-staged microfluidic technology with polyethyleneimine-polycaprolactone (PEI-PCL) in organic phase further coated over gene-loaded neutral lipid layer. Due to the lipid membrane coating, the core-shell contains reversed micelle via hydrophobic interaction, resulting in enhanced stability in vivo. Reprinted with permission from [136], Copyright © 2020, American Chemical Society.CC BY · PubMed Central
Figure 12 A multiparous lipid-PLGA hybrid nanoparticle synthesis for diagnosis and treatment. Reprinted with permission from [143], Copyright © 2019, American Chemical Society.
Figure 12 A multiparous lipid-PLGA hybrid nanoparticle synthesis for diagnosis and treatment. Reprinted with permission from [143], Copyright © 2019, American Chemical Society.CC BY · PubMed Central
Figure 13 Multifunctional co-delivery by PLHNPs system in cancer immunotherapy. (A) Mannose receptor targeted hybrid vaccine system via PCL-PEG-PCL polymer with the help of cationic lipid DOTAP. The loaded IMQ (a TLR7/8 agonists), monophosphoryl lipid A (MPLA—a TLR4 agonist), and anionic OVA antigen containing the hybrid system were internalized by immature DC (dendritic cells). (B) Due to the strong antigen presentation by DC, MHC I and MHC II molecules increase the antigen peptide synthesis, along with the release of TLR4 and TLR7/8 in extracellular and intracellular response following endosomal escape. The upregulation of several inflammatory cytokines leads to innate immune system activation through highly adaptive Th1 cell immunity. The synergistic effect of both TLR agonist and the antigen promoted the activation of both B and T cells in both cellular and humoral immune responses. Reproduced with the permission from [147], Copyright © 2019, American Chemical Society.
Figure 13 Multifunctional co-delivery by PLHNPs system in cancer immunotherapy. (A) Mannose receptor targeted hybrid vaccine system via PCL-PEG-PCL polymer with the help of cationic lipid DOTAP. The loaded IMQ (a TLR7/8 agonists), monophosphoryl lipid A (MPLA—a TLR4 agonist), and anionic OVA antigen containing the hybrid system were internalized by immature DC (dendritic cells). (B) Due to the strong antigen presentation by DC, MHC I and MHC II molecules increase the antigen peptide synthesis, along with the release of TLR4 and TLR7/8 in extracellular and intracellular response following endosomal escape. The upregulation of several inflammatory cytokines leads to innate immune system activation through highly adaptive Th1 cell immunity. The synergistic effect of both TLR agonist and the antigen promoted the activation of both B and T cells in both cellular and humoral immune responses. Reproduced with the permission from [147], Copyright © 2019, American Chemical Society.CC BY · PubMed Central

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Metadata

Authors
Mohanty, A., Uthaman, S., & Park, I.-K.
Venue
Molecules
Publisher
MDPI AG
Published
2020-09-23
Volume
25
Issue
19
Pages
4377
ISSN
1420-3049
DOI
10.3390/molecules25194377
PMC
PMC7582728
Cited by
160
References
6
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
National Research Foundation of Korea (2017M3A9E2056372, 2020R1A2C2005620, 2018R1A5A2024181 and 2019M3E5D1A02068082)

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