Liposomes — microscopic phospholipid bubbles with a bilayered membrane structure — have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs — from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Recent advances with liposomes as pharmaceutical carriers.

Among several promising new drug-delivery systems, liposomes represent an advanced technology to deliver active molecules to the site of action, and at present several formulations are in clinical use. Research on liposome technology has progressed from conventional vesicles ("first-generation liposomes") to "second-generation liposomes", in which long-circulating liposomes are obtained by modulating the lipid composition, size, and charge of the vesicle. Liposomes with modified surfaces have also been developed using several molecules, such as glycolipids or sialic acid. A significant step in the development of long-circulating liposomes came with inclusion of the synthetic polymer poly-(ethylene glycol) (PEG) in liposome composition. The presence of PEG on the surface of the liposomal carrier has been shown to extend blood-circulation time while reducing mononuclear phagocyte system uptake (stealth liposomes). This technology has resulted in a large number of liposome formulations encapsulating active molecules, with high target efficiency and activity. Further, by synthetic modification of the terminal PEG molecule, stealth liposomes can be actively targeted with monoclonal antibodies or ligands. This review focuses on stealth technology and summarizes pre-clinical and clinical data relating to the principal liposome formulations; it also discusses emerging trends of this promising technology.

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Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential.

http://www.chtf.stuba.sk/~szolcsanyi/education/files/Organicka%20chemia%20II/Prednaska%208_Aminokyseliny%20a%20peptidy/Doplnkove%20studijne%20materialy/Amide%20bond%20formation/Amide%20bond%20formation.pdf

Amide bond formation and peptide coupling

Sodium triacetoxyborohydride is presented as a general reducing agent for the reductive amination of aldehydes and ketones. Procedures for using this mild and selective reagent have been developed for a wide variety of substrates. The scope of the reaction includes aliphatic acyclic and cyclic ketones, aliphatic and aromatic aldehydes, and primary and secondary amines including a variety of weakly basic and nonbasic amines. Limitations include reactions with aromatic and unsaturated ketones and some sterically hindered ketones and amines. 1,2-Dichloroethane (DCE) is the preferred reaction solvent, but reactions can also be carried out in tetrahydrofuran (THF) and occasionally in acetonitrile. Acetic acid may be used as catalyst with ketone reactions, but it is generally not needed with aldehydes. The procedure is carried out effectively in the presence of acid sensitive functional groups such as acetals and ketals; it can also be carried out in the presence of reducible functional groups such as C−C multi...

Reductive Amination of Aldehydes and Ketones with Sodium Triacetoxyborohydride. Studies on Direct and Indirect Reductive Amination Procedures1

Nanoparticles show their promise for improving the efficacy of drugs with a narrow therapeutic window or low bioavailability, such as anticancer drugs and nucleic acid-based drugs. The pharmacokinetics (PK) and tissue distribution of the nanoparticles largely define their therapeutic effect and toxicity. Chemical and physical properties of the nanoparticles, including size, surface charge, and surface chemistry, are important factors that determine their PK and biodistribution. The intracellular fate of the nanoparticles after cellular internalization that affects the drug bioavailability is also discussed. Strategies for overcoming barriers for intracellular delivery and drug release are presented. Finally, future directions for improving the PK of nanoparticles and perspectives in the field are discussed.

Pharmacokinetics and biodistribution of nanoparticles.

Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs.

Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less myelotoxic than doxorubicin. Typical forms of toxicity associated to it are acute infusion reaction, mucositis and palmar plantar erythrodysesthesia, which occur especially at high doses or short dosing intervals. Active and cell targeted liposomes can be obtained by attaching some antigen-directed monoclonal antibodies (Moab or Moab fragments) or small proteins and molecules (folate, epidermal growth factor, transferrin) to the distal end of polyethylene glycol in pegylated liposomal doxorubicin. The most promising therapeutic application of liposomes is as non-viral vector agents in gene therapy, characterized by the use of cationic phospholipids complexed with the negatively charged DNA plasmid. The use of liposome formulations in local-regional anticancer therapy is also discussed. Finally, pegylated liposomal doxorubicin containing radionuclides are used in clinical trials as tumor-imaging agents or in positron emission tomography.

From conventional to stealth liposomes: a new frontier in cancer chemotherapy.

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel

In this review, the different types of liposome used in medicine, in particular in the field of antitumor therapy, are focalised, emphasizing their structures, pharmacological action, pharmacokinetics and biodistribution, toxicity profiles and in the main clinical applications. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome, and Myocet, doxorubicin-containing liposome used in clinical trials to treat metastatic breast cancer. The last generation liposomes were pegylated liposomal doxorubicin (Caelix), called "stealth liposomes" because of their ability to evade interception by the immune system, characterized by very long-circulation half-life, favourable pharmacokinetic behaviour and specific accumulation in tumor tissues.

Maurizio Ceruti

Papers

Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing lipophilic gemcitabine prodrugs.

From conventional to stealth liposomes: a new frontier in cancer chemotherapy.

Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel

From conventional to stealth liposomes: a new Frontier in cancer chemotherapy.