Application of liposomal technologies for delivery of platinum analogs in oncology

Figures & data

Table 1 Platinum-based anticancer drugs used in the clinic

	Molecular formula and structure	Manufacturer/distributor	Dose-limiting toxicity	Clinical status and indications
Cisplatin		Generic	Nephrotoxicity	Approved worldwide (sarcomas, small cell lung cancer, ovarian cancer, lymphomas, and germ cell tumors)
Carboplatin		Generic	Myelosuppression	Approved worldwide (ovarian carcinoma, lung, head and neck cancers)
Oxaliplatin		Sanofi S.A., Paris, France	Neurotoxicity	Approved worldwide (colorectal cancer, advanced gastric and ovarian cancers)
Nedaplatin		Shionogi Pharmaceuticals, Osaka, Japan	Myelosuppression	Approved in Japan (head and neck, lung small cell, bladder, ovary, esophagus and cervix cancer)
Heptaplatin		SK Chemicals Life Sciences, Seongnam, South Korea	Nephrotoxicity, intra-abdominal bleeding	Approved in Korea (gastric cancer)
Lobaplatin		Asta-Medica GmbH, Dresden, Germany	Thrombocytopenia	Approved in the People’s Republic of China (chronic myelogenous leukemia, inoperable, metastatic breast, small cell lung cancer)

Table 2 Clinically evaluated liposomal formulations of platinum drugs

Formulation	L-NDDP	SPI-77	Lipoplatin	Lipoxal	LiPlaCis
Encapsulated drug	NDDP	Cisplatin	Cisplatin	Oxaliplatin	Cisplatin
Lipid composition	DMPC/DMPG	HSPC/cholesterol/DSPE-PEG2000	HSPC/DPPG/DSPE-PEG2000	NA	DSPC/DSPG/DSPE-PEG2000
Particle size	1–5 μm	110 nm	110 nm	NA	NA
Drug-to-lipid weight ratio	1:15	1:70	1:10	NA	NA
Half-life in animals (hours)	NA	16	7	NA	NA
Half-life in humans (hours)	t1/2α, 0.8–21 min t1/2β, 14–36	80–145	60–117	24–35	t1/2α, 3–5.5 t1/2β, 80–141
MTD (mg/m^2)	312.5	420	300	300	120
Clinical status	Phase II	Phase II	Phase II, III	Phase I	Phase I
Indications	Colorectal cancer, malignant pleural mesothelioma	Ovarian, non-small cell lung, and head and neck cancer	Pancreatic cancer, head and neck cancer, mesothelioma, breast, gastric and non-small cell lung	Advanced gastrointestinal tract cancer	NA
References	^Citation43^–^Citation50	^Citation52^–^Citation58	^Citation59^–^Citation66	^Citation67	^Citation68

Abbreviations: MTD, maximum tolerated dose; NDDP, cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II); DMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); HSPC, hydrogenated soy phosphatidylcholine; DSPE-PEG2000, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (ammonium salt); DPPG, 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); NA, not available; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; DSPG, 1,2-distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (sodium salt); min, minutes.

Figure 1 Cytotoxicity towards human ovarian carcinoma cells. (A) Lipid suspension of cisplatin (cisPt-phosphatidylserine/phosphatidylcholine) (▴), conventional cisplatin (∎), conventional cisplatin mixed with a blank lipid suspension (◻), and blank lipid suspension (dashed line). (B) Variations on the standard protocol, omitting freeze-thaw (▵), omitting phosphatidylserine (엯). (C) Proposed mechanism of nanocapsule formation and cell interaction.

Note: Adapted by permission from Macmillan Publishers Ltd: Nature Medicine,⁶⁹ copyright 2002.

Figure 2 (A) Layer-by-layer assembly of nanoparticles and chemical structures of the anionic and cationic lipids. (B) Transmission electron microscopic image of anionic nanoparticles (NP−) after uranyl acetate negative staining. (C) Transmission electron microscopic images of cationic nanoparticles (NP+) after uranyl acetate negative staining. Arrows indicate the multilayer. Scale bar, 50 nm. (D) Cytotoxic effect on IGROV-1 cancer cell line. (E) Comparison of cytotoxicity of cisplatin-loaded NP+ nanoparticles compared with free cisplatin in various human carcinoma cell lines.

Note: Adapted with permission from Khiati S, Luvino D, Oumzil K, Chauffert B, Camplo M, Barthélémy P. Nucleoside-lipid-based nanoparticles for cisplatin delivery. ACS Nano. 2011;5(11):8649–8655. Copyright (2011) American Chemical Society.⁷⁰

Figure 3 Plasma clearance (A) and biodistribution (B) of L-OHP, bare liposomes, PEG liposomes, and TF-PEG liposomes after intravenous injection. (C) Comparison of tumor growth suppression with free L-OHP and liposomes encapsulating L-OHP in a Colon-26 mouse model.

Note: Reprinted from International Journal of Pharmaceutics. Vol 346(1–2). Suzuki R, Takizawa T, Kuwata Y, et al. Effective anti-tumor activity of oxaliplatin encapsulated in transferrin PEG-liposome, pages 143–150. Copyright (2008), with permission from Elsevier.⁷³

Abbreviations: PEG, polyethylene glycol; TF, transferrin; L-OHP, oxaliplatin; h, hours.

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