Liposome-targeted delivery for highly potent drugs

Figures & data

Figure 1. Schematic representation of the different types of liposomal drug delivery systems including (A) conventional (B) PEGylated (C) ligand-targeted and (D) theranostic liposomes. In addition, the site of hydrophobic and hydrophilic drug placing has shown. (Taken from Susan Hua work, with permission from author and journal) (Sercombe et al., 2015).

Table 1. Highly potent chemical drugs delivered using targeted liposomes.

Drug	Targeting ligand	Receptor	Explanation	References
Cisplatin	– Tf. – 26-mer DNA aptamer – cRGDyk (RGD peptide)	– TfR – Nucleolin (NCL) a bcl-2 mRNA-binding protein – Integrin receptors	Binding to DNA and results in DNA strands cross-linking and apoptosis	[Iinuma et al. 2002, Krieger et al. 2010] [Cao et al. 2009] [Wang et al. 2014]
Oxaliplatin	– Cetuximab (CTX), a mAb – Tf	– epidermal growth factor receptor (EGFR) – TF receptor	A platinum-based antineoplastic agent that inhibits DNA synthesis in cells	[Zalba et al. 2015] [Maruyama 2011]
Paclitaxel	– Herceptin – Hyaluronic acid (HA) – Folate – RGD peptide	– HER2 – Cluster of differentiation 44 (CD44) – Folate receptor (FR) – Integrin receptors	A cytoskeletal drugs that target tubulin and generally cause apoptosis	[Yang et al. 2007] [Ravar et al. 2016] [Wu et al. 2006] [Zhao et al. 2009]
Epirubicin	– C225-Fab′ – PTD (HIV-1) peptide– Tf	– EGFR or EGFR variant III (EGFRvIII) – Heparan sulfate receptors and the positively charged amino acids – TfR	Intercalating DNA strands result in inhibiting DNA and RNA syntheses which lead to cell death.	[Mamot et al. 2005] [Ju et al. 2014] [Gandhi et al. 2015]
Lonidamine	– Dequalinium (DQA)	– Mitochondrial molecule	Inhibitboth respiration and glycolysis under conditions of hypoxia leading to a decrease in cellular ATP and causes apoptosis.	[Li et al. 2013]
Doxorubicin	– hCTMO1 mAb – Tf – Folic acid – Hyaluronan (HA) – RNA aptamer	– MUC-1 antigen – TfR – Float receptor – CD44 – Prostate-specific membrane antigen (PSMA)	Intercalating DNA and inhibit macromolecular biosynthesis and stop the process of DNA replication.	[Al-Ahmady et al. 2014] [Wu et al. 2007] [Goren et al. 2000] [Eliaz and Szoka 2001] [Baek et al. 2014]
Daunorubicin	– P-aminophenyl-α-D-manno-pyranoside(MAN) and Tf	– Stereo-specific glucose carriers and TfR	Act similar to doxorubicin and slows or stops the growth of cancer cells in the body.	[Ying et al. 2010]
Deferoxamine	– Float	– Float receptor	Binding iron and inactivates P4H and interferes with the collagen synthesis machinery and reduce excessive collagen deposition.	[Mathias et al. 1996]
Indinavir	– Anti-HLA-DR Fab□ fragments	– HLA-DR-expressing cells	A protease inhibitor used as a highly active antiretroviral component.	[Gagné et al. 2002]
Vincristine	– mBAFF – Anti-CD19 IgG2a	– BAFF receptor – CD19 epitope at the cell surface	During the metaphase binds to the tubulin protein and stops the cell from separating its chromosomes leading to apoptosis.	[Zhang et al. 2008] [Sapra et al. 2004]
Ceramides	– Tf	– TfR	Enhances membrane rigidity and stabilizes smaller lipid platforms and participates in a cellular signaling, includes cell death	[Koshkaryev et al. 2012]
Mitoxantrone	– LHRH analogs	– LHRH receptors	A type-II topoisomerase inhibitor; disrupts DNA synthesis and DNA repair	[He et al. 2010]
Irinotecan	– Folic acid – Octreotide	– Float receptor – Somatostatin receptor	Prevents DNA from unwinding by inhibition of topoisomerase	[Zhang and Yao 2012] [Iwase and Maitani 2010]

Table 2. Highly potent protein and peptide drugs delivered using targeted liposomes.

Active targeted liposomal protein and peptide
Protein/Peptide	Target moiety	Therapy	References
RGD peptide plus streptokinase	RGD	Arterial thrombi	[Vaidya et al. 2011]
Monoclonal IgG2a antibody 34A	Monoclonal IgG2a antibody 34A	Lung cancer	[Maruyama et al. 1997]
Monoclonal IgG1, antibody 21B2	Monoclonal IgG1, antibody 21B2	Solid tumors	[Maruyama et al. 1997]
EYFP and CNA35	Cysteine		[Reulen et al. 2007]
Growth factors such as NTs, GDNF, VEGF, FGF2, EGF	TAT, RVG, and transferrin receptor antibody	Ischemic stroke	[Rhim and Lee 2016]
Eptifibatide	RGD	Atherosclerosis	[Bardania et al. 2016a,b]
Codelivery/passive targeted liposomal protein and peptide
Protein/peptide	Drugs	Therapy	References
IL-2 plus transforming growth factor-β (TGF-β)^a		Tumor immunotherapy	[Park et al. 2012]
γ-Interferon (INF-γ)	Cisplatin	Cancer of the sigmoid colon andmetastatic nodules in the liver	[Kohara et al. 1995]
Tumor necrosis factor-a (TNF)	Liposomal DOX	Soft-tissue sarcoma	[Ten Hagen et al. 2002]
IL-2	–	Hepatic metastases	[Kanaoka et al. 2002]
Calcitonin	–	Assessment of mucoadhesive function for oral administration	[Takeuchi et al. 2003]
Vasoactive intestinal peptide (VIP)	–	Chronic ocular pathologies such as autoimmune uveitis	[Lajavardi et al. 2009]
Asialoerythropoietin (AEPO)	–	Cerebral ischemia–reperfusion (I/R)	[Ishii et al. 2012]
Insulin	–	Diabetes mellitus-oral route-intestinal route-pulmonary route	[Jain et al. 2007] [Bi et al. 2008] [Ramadas et al. 2000]
Recombinant IL-2	–	Immunoregulatory response in cancer	[Kanaoka et al. 2001]
Myelin basic protein (MBP)	–	Allergic encephalitis	[Belogurov et al. 2013]
Superoxide dismutase (SOD)	–	Rheumatoid arthritis, cancer, and respiratory distress syndrome	[Xu et al. 2012]
CD39	–	Thromboregulatory	[Haller et al. 2006]

^a TGF-β receptor-I inhibitor represents a role of a small hydrophobic protein drug molecule via blockade signaling and its combination with IL-2 in liposomes, induce antitumor responses.

Table 3. Highly potent nucleic acid therapeutics delivered using targeted liposomes.

Therapeutic gene	Targeted moiety	Application	References
siRNA	– Vitamin A – RGD peptide Aptamer	– Fibrosis associated with chronicpancreatitis – Cancer RNAi therapy melanomas treatment	[Ishiwatari et al. 2013] [Yonenaga et al. 2012]
Plasmid DNA	– Transferrin – HIV-1 Tat protein – Folate – RI7/8D3 MAbs – TAT peptide – Anti-TfR scFv – RGD peptide	– Amplify transfection efficacy in gene delivery via enhancement in endocytosis and fusion – Cell-specific gene transfer – Human oral and prostate cancer treatment – Targeted gene therapy including vector-specific transient transfection – Localized in vivo gene therapy and transfection with various protocols of cell – Systemic gene therapy of various human cancers – Gene therapy	[Simoes et al. 1999] [Hyndman et al. 2004] [Hattori and Maitani 2004] [Rivest et al. 2007] [Torchilin et al. 2003] [Xu et al. 2002] [Majzoub et al. 2014]
miRNA/siRNA	– GC4 scFv	– Targeted cancer therapy	[Chen et al. 2010]
Oligonucleotides	– CD20 Ab (rituximab) – Transferrin Aptamer	– Treatment of chronic lymphocytic leukemia – Treatment of Acute myelogenous leukemia (AML) and chronic myeloid leukemia treatment selectively targeting and introducing CpG into CT26 carcinoma cells,	[Yu et al. 2013] [Mendonça et al. 2009, Zhang et al. 2009] [Liu et al. 2016]
Codelivery
Gene + Drug	Target moiety	Application	References
siRNA + DOX	– Anisamide (AA) ligand	– Overcome drug resistance in cancer treatment	[Chen et al. 2010]
GFP plasmid + calcein	– Folate ligand	– Drug delivery and gene transfection	[Javadi et al. 2013]
siRNA + DOX	– Folate receptor	– Tumor targeting and cancer treatment	[Yang et al. 2014]

Table 4. Examples of ligand-targeted nanoliposome formulations undergoing clinical evaluation (Goodall et al. 2015, van der Meel et al. 2013).

Ligand	Product name	Bioactive compound	Type of drug	Clinical indication	Phase
Antitransferrin receptor scFv	SGT-53	p53 gene	Nucleic acid	Solid tumors	Phase II
Antibody fragment (Fab′)	Anti-EGFR ILs-DOX	Doxorubicin	Chemical	Solid tumors	Phase I
Single domain antibody (dAb) fragment (VH)	Lipovaxin-MM	Melanoma antigens + IFNγ	Proteins	Melanoma vaccine	Phase I
Transferrin	MBP-426	Oxaliplatin	Chemical	Gastroesophageal adenocarcinoma	Phase II
Antibody fragment (scFv)	MM-302	Doxorubicin	Chemical	Breast cancer	Phase I
Antibody fragment (scFv)	SGT-94	RB94 plasmid DNA	Nucleic acid	Solid tumor	Phase I

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