Table 2.
In vivo studies of aerosolised liposomal formulations and their parameters in animals and humans for treating lung cancer
| Therapeutic agent | Delivery device | Type of liposome used | Subject | Study phase | Adverse effects | Dose and regiment | Monitoring of tumour | Ref. |
|---|---|---|---|---|---|---|---|---|
| Cisplatin | PARI LC Star jet nebuliser | DPPC | Human | Phase I | Nausea, vomiting, dyspnoea, fatigue and hoarseness No DLT reached |
Escalation from 1.5 mg/m2 until DLT for 1 – 4 consecutive days every 1 – 3 weeks | Clinical examination, standard blood and urinary tests, PFT, CXR and CT of the thorax | 86 |
| 9-NC | AeroMist nebuliser | DLPC | Human | Phase I/II | Nausea, vomiting, cough, bronchial irritation, fatigue, anaemia, neutropenia DLT reversible grade 3 or 4 haematological toxicity, grade 2 neurotoxicity and grade 3 non-myelosuppressive toxicity |
0.25 – 1 mg/m2/day, 5 days per week for 8 weeks | Pulse oximeter readings daily, weekly CBC, monthly blood chemistry tests, and urine analysis. Tumour markers and a computer-assisted tomography scan of the chest were obtained at baseline and before each course. Simple spirometry, DLCO and lung volumes before and after first aerosol exposure | 32, 108 |
| IL-2 | Puritan Bennett twin jet nebuliser | DMPC | Human | Phase I | No significant adverse effects | 1.5, 3.0 and 6.0 × 106 IU of IL-2 three times a day for 8 – 84 days | Physical examination, CXR, CBC, electrolytes, BUN, creatinine, AST, ALP, bilirubin, LDH, DLCO and PFT | 31 |
| IL-2 | Puritan Bennet Twin Jet Nebuliser | DMPC | Animal (dogs) | – | Mild cough immediately after aerosolisation treatments | 1 × 106 IU of IL-2 twice daily for 15 days and then 1 × 106 IU of IL-2 three times daily for 15 days or 1 × 106 IU of IL-2 twice daily for 30 days | Physical examination, CBC, serum biochemistries (including concentration of albumin, total protein, ALT, ALP, AST, total bilirubin, BUN, creatinine, electrolytes) urinalyses, biopsy | 84 |
| 9-NC | AeroTech II nebuliser flowing to mice in a nose-only exposure chamber | DLPC | Animal (mice) | – | Skin lesions, weight loss | 0.1 – 1.0 mg/kg daily, 5 days per week for 36 – 49 days | Tumour size or volume measured by calipers | 90 |
| 9-NC and polyethyleneimine-p53 DNA (PEI-p53) | AeroTech II nebuliser | DLPC | Animal (mice) | – | Not recorded | 0.5 mg/1 ml twice a week for 2 weeks and 2 mg plasmid/10 ml once a week for 2 weeks | Lung weight | 76 |
| 9-NC | AeroTech II nebuliser | DLPC | Animal (mice) | – | Not recorded | 1- to 2-hour aerosol exposure 5 times weekly for 16 – 17 days Total deposited dose 2.3 – 3.7 mg/kg | Lung weight | 89 |
| 9-NC | AeroMist nebuliser | DLPC | Animal (mice) | – | Not recorded | 1- to 2-hour aerosol exposure 5 times weekly for 16 – 21 days Total deposited dose 2.3 – 3.7 mg/kg | Lung weight | 91 |
| Vitamin E analogue (a-TEA) and 9-NC | AeroTech II nebuliser | DLPC | Animal (mice) | – | Not recorded | Treatment course was 7 days per week for 3 weeks | Tumours were measured using calipers every other day | 93 |
| PTX | AeroMist nebuliser | DLPC | Animal (mice) | – | Not recorded | Total of 1.4 – 7.8 mg/kg of PTX were deposited in the lungs (dose regiment: 3 times per week for 3 weeks) | Lungs were resected and weighed | 102 |
| PTX together with cyclosporine A | AeroMist nebuliser | DLPC | Animal (mice) | – | Weight loss | Total of 1.4 – 7.8 mg/kg of PTX and 1.1 – 6.1 mg/kg of CA were deposited in the lungs (dose regimen: 3 times per week for 3 weeks) | Lungs were resected and weighed | 102 |
| PTX | AeroMist nebuliser | DLPC | Animal (mice) | – | Aggressiveness | Total of 5 mg/kg during a 30-min period were administered | Lungs were resected and weighed | 80, 104 |
| DOX | Collison nebuliser connected to four-port, nose-only exposure chambers | DLPC | Animal (mice) | – | Alterations of normal pulmonary parenchyma characterised by alveolar haemorrhage | 2.5 mg/kg for single inhalation every third day for 24 days | Tumour growth was monitored by bioluminescent IVIS (Xenogen) and ultrasound Vevo 2100 (VisualSonics) imaging systems | 104 |
| DOX combined with antisense oligonucleotides | Collison nebuliser connected to four-port, nose-only exposure chambers | DLPC | Animal (mice) | – | None | 2.5 mg/kg for single inhalation of DOX with 0.125 mg/kg antisense oligonucleotides every third day for 24 days | Tumour growth was monitored by bioluminescent IVIS (Xenogen) and ultrasound Vevo 2100 (VisualSonics) imaging systems | 104 |
| Camptothecin | Aerotech II nebuliser | DLPC | Animal (mice) | – | Not recorded | 81 µg/kg inhalation for 30 min only | Lungs were resected and weighted | 109 |
| DOX-liposomes | Collison jet nebuliser | EPC-Chol, DSPE-PEG | Animal (mice) | – | Very limited compared to free drug formulation | 14 µg/kg inhalation in combination with 2.5 mg/kg i.v. injection. This was compared with intravenous injection alone | Apoptosis induction in different organs (the lungs with tumour, liver, kidney, spleen, heart and brain) was measured using Cell Death Plus ELISA kit | 106 |
| DOX encapsulation in transferrin conjugated PEG liposomes | Intracorporeal nebulising catheter | Animal (athymic Rowett nude rat) | – | Not recorded | 0.2 – 0.4 mg/kg | Animal survival rate | 107 | |
5-FU = 5-Fluorouracil; CXR = chest X-ray; PFT = pulmonary function test; CBC = complete blood count; BUN = blood urea nitrogen; AST = aspartate transaminase; ALP = alka-line phosphatase; ALT = alanine transaminase; LDH = lactate dehydrogenase; DLCO = diffusing capacity of the lung for carbon monoxide; LNP = lipid-coated nanoparticles; DPPC = dipalmitoylphosphatidylcholine; DLPC = dilauroylphosphatidylcholine; DMPC = dimyristoylphosphatidylcholine; EPC-Chol = egg phosphatidylcholine with cholesterol; DSPE-PEG = pegylated distearoyl phosphatidylethanolamine.