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Lung cancer inhalation therapeutics
Published in Anthony J. Hickey, Heidi M. Mansour, Inhalation Aerosols, 2019
Nonviral carriers are safer than viral carriers, but they have lower transfection efficiency. Among the several cationic polymers, polyethyleinimine (PEI) achieves higher transfection efficiency both in tissue culture and in vivo. Selective gene expression occurs in the lungs of mice after IL-12 gene administration in PEI-based polyplexes for treatment of osteosarcoma lung metastasis (162). The growth of lung metastasis was inhibited by aerosolized PEI-p53 complexes, and animals survived longer than the control group (163). Similarly, a modified PEI-p53 complex (p53CD[1–366]) or PEI-IL12 interfered with the growth of osteosarcoma lung metastasis without producing toxicity or signs of inflammation even after repeated exposures (162,164). However, the cytotoxicity of PEI depends on its molecular weight and configuration (165,166). Several cationic lipids, such as dioleoyltrimethylammonium propane (DOTAP) and dioleyloxypropyltrimethylammonium (DOTMA), have been employed as gene carriers, with DOTMA having higher transfection efficiency than DOTAP. Mixing cationic lipids with neutral lipids facilitates formation of liposomes and enhances their disassembly after uptake into the cell. Notably, a significant drawback of cationic lipoplexes is that high doses could trigger inflammatory responses in the lung. To avoid such toxicity, investigators employed biodegradable polymer-based NPs, which have a prolonged residence time in the lung, as gene carriers.
Pharmacokinetics of Nanocarrier-Mediated Drug and Gene Delivery
Published in Mansoor M. Amiji, Nanotechnology for Cancer Therapy, 2006
Yuriko Higuchi, Shigeru Kawakami, Mitsuru Hashida
PC exclusively expresses large numbers of high affinity cell-surface receptors that can bind asialoglycoprotein and internalize to the cell interior. In order to achieve PC-specific gene transfection, galactose moieties are introduced into the cationic liposomes. The galactosylation of liposomes can be achieved by coating with either glycoproteins or galactose conjugated synthetic lipids. Hara et al.96 reported that asialofetuin-labeled liposomes encapsulating pDNA were taken up by asialoglycoprotein receptor-mediated endocytosis using cultured PC and showed the highest hepatic gene expression after intraportal injection with a preloading of EDTA. Gal-C4-Chol that possess a similar structure to Man-C4-Chol was synthesized.58 In vivo gene transfer was examined by optimizing the pharmacokinetics and physicochemical properties.97 The radioactivity in the liver from the Gal-liposome/[32P] pDNA complex (Gal-lipoplexes) was about 75% of the dose even 1 min after intraportal administration. The hepatic gene expression of Gal-lipoplexes was more than a 10-fold greater than that of lipoplexes with bare cationic liposomes. When gene expression was examined at the intrahepatic cellular level, the gene expression of PC of Gal-lipoplexes was significantly higher than that of liver NPC. On the other hand, the gene expression of PC and NPC of lipoplexes was almost identical. In addition, asialoglycoprotein receptor-mediated endocytosis was also confirmed by the inhibitory effect of pre-dosing an excess amount of galactosylated bovine serum albumin. It was previously reported that the lipoplexes interact with erythrocytes after intravenous administration.88 Recently, the presence of an essential amount of sodium chloride (NaCl) during the formation of Gal-lipoplexes stabilizing the complexes in accordance with the surface charge regulation (SCR) theory was demonstrated.98 The transfection activity in hepatocytes of SCR Gal-lipoplexes was significantly higher than that of conventional complexes.
Immune to addiction: how immunotherapies can be used to combat methamphetamine addiction
Published in Expert Review of Vaccines, 2021
Md Kamal Hossain, Majid Hassanzadeganroudsari, Erica Kypreos, Jack Feehan, Vasso Apostolopoulos
A number of nicotine-conjugated vaccines have been used in clinical trials; however, all of them were unsuccessful due to inadequate antibody production [45]. In a novel approach, a liposome-BSA protein-based nanocarrier system was developed for the delivery of a nicotinic hapten (liposome-Nicotinic hapten-BSA; named lipoplex [45]). Lipoplex, along with Alum as an adjuvant, demonstrated high anti-nicotine antibody titers (111,169 ± 2,112) in mice compared to Nicotinic hapten-BSA without liposomes mixed with Alum adjuvant. The new generation of lipoplexes contains a carbon backbone based on a specific nanoparticle called a ‘nanohorn’. It enhances the stability of the liposome structure and provides higher level of anti-nicotine antibodies compared to traditional nicotine-BSA complex on backbone-free lipoplexes [46]. Lipoplex has strong drug loading capability along with efficient delivery of the vaccine to the cell surface. This approach has not yet to be explored for anti-METH immunotherapies and could be a potential area for future research.
Lipoplex-based therapeutics for effective oligonucleotide delivery: a compendious review
Published in Journal of Liposome Research, 2020
Pirthi Pal Singh, Veena Vithalapuram, Sunita Metre, Ravinder Kodipyaka
This review focuses on the lipid-based system (especially lipoplex) considering its potential by fast entry and growth in clinical trial programs and recent regulatory approval of Patisiran lipid complex. Using literary examples, the insights on the versatility of types of lipids, their effect on lipoplex formation and morphology is provided. The importance of physicochemical properties in understanding correlation between formulation parameters and activity of lipoplexes in-vitro as well as in-vivo are discussed in detail. The factors influencing the structure, stability, internalization, and transfection of the lipoplex required for effective lipoplex delivery system are explored. Furthermore, safety considerations and the status of lipoplexes and other lipid nano-carriers in clinical trials are also being discussed.
Efficient anti-tumor nano-lipoplexes with unsaturated or saturated lipid induce differential genotoxic effects in mice
Published in Nanotoxicology, 2019
Hari Krishnareddy Rachamalla, Sujan Kumar Mondal, Shruti S. Deshpande, Kathyayani Sridharan, Kalpana Javaji, Madan Mohan Chandra Sekhar Jaggarapu, Sudhakar Jinka, Vishnusravan Bollu, Sunil Misra, Rajkumar Banerjee
It is evident from the previous study that the D1XE-lipoplex has favorable physical and biophysical properties than DXE-lipoplex. But it is important to review through preclinical studies the toxic effects (if any) of these lipoplexes and compare toward establishing its beneficial and potential clinical use. For this, we kept different groups of mice (males and females under each group), wherein two groups lipoplexes and the placebo or negative control (0.9% NaCl) were injected seven times, but cyclophosphamide (CP), a known toxic, the anticancer drug was injected in a standard amount only once. To compare the genotoxic effects due to single and multiple injections, we included two more groups: single injections of 0.9% NaCl and DXE-lipoplex. For all genotoxicity studies, the number of respective lipoplexes’ contents including the encapsulated anticancer drug (ESC8, 3.73 mg/kg body weight) are same and equal to what has been tested in tumor-bearing mice. Before genotoxicity studies in bone marrow cells to begin, we accomplished cell cycle analyses of bone marrow cells of treated mice (Figure S4). Therein, we show that there are no significant changes in cell cycle pattern for control and D1XE-lipoplex treatment for both male and female populations. However, DXE-lipoplex, irrespective of gender, showed a decreased number of G0/G1 phase cells and significantly increased numbers of G2/M phase cells compared to D1XE-lipoplex. CP induced much more G2/M arrests than all other groups. The data indicate that D1XE-lipoplex is relatively safer for bone marrows than DXE-lipoplex and CP. We also found that D1XE-lipoplex induced less intracellular ROS than DXE-lipoplex in CHO cells (Figure S5), clearly indicating that D1XE-lipoplex induces lesser ROS-induced clastogenic and aneugenic effects, especially on bone marrow cells.