Dmitri B. Kirpotin

Anti-HER2 immunoliposomes for targeted therapy of human tumors

Anti-HER2 immunoliposomes (ILs) have been constructed by conjugation of Fab fragments of recombinant humanized monoclonal antibody rhuMAbHER2 to small sterically stabilized unilamellar liposomes, to create a targeted drug delivery vehicle for the treatment of HER2 (c-erbB-2, neu)-overexpressing cancers. Parameters affecting in vitro binding and internalization of ILs include liposome composition, Fab linkage site and Fab density. Anti-HER2 ILs have been constructed to optimize intracellular drug delivery. Doxorubicin (dox)-loaded ILs are highly stable and exhibit prolonged circulation in rats. In nude mice bearing HER2-overexpressing tumor xenografts, anti-HER2 ILs administered i.v. resulted in efficient tumor localization, with penetration of the ILs throughout the tumor mass and accumulation within tumor cells. In contrast, non-targeted liposomes resulted in extracellular tumor accumulation only. In multiple HER2-overexpressing human breast tumor xenograft models, treatment with dox-loaded anti-HER2 ILs produces significantly increased antitumor cytotoxicity as compared to free dox or dox-loaded non-targeted liposomes and significantly less systemic toxicity than free dox. To explore further the intracellular delivery advantages of ILs, anti-HER2 ILs bearing cationic lipids are being developed for nucleic acid delivery. These cationic immunoliposomes mediate efficient and specific transfection of target cells with reporter genes, as well as intracellular delivery of labeled oligonucleotides. Thus, anti-HER2 ILs represent an efficient and feasible strategy to achieve targeted intracellular delivery of therapeutic agents.

Liposomes with detachable polymer coating: destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage of surface-grafted poly(ethylene glycol)

Plasma‐stable liposomes (100 nm) were prepared from dioleoylphosphatidylethanolamine (DOPE) and 3–6 mol% of a new disulfide‐linked poly(ethylene glycol)‐phospholipid conjugate (mPEG‐DTP‐DSPE). In contrast to similar preparations containing non‐cleavable PEG‐phospholipid conjugate, thiolytic cleavage of the grafted polymer chains facilitated rapid and complete release of the liposome contents. Furthermore, the detachment of PEG from DOPE liposomes resulted in liposomal fusion. Finally, while formulation of pH‐sensitive DOPE/cholesterol hemisuccinate liposomes with mPEG‐DTP‐DSPE abolished the pH sensitivity, cleavage of the PEG chains completely restored this property. These are the first examples of new useful properties of liposomes grafted with cleavable polymer.

Immunoliposomes for cancer treatment.

Publisher Summary Immunoliposomes represent a rational strategy to achieve targeted drug delivery for cancer treatment. This chapter summarizes the recent developments in the use of immunoliposomes for cancer treatment. Because of their improved pharmacologic properties, sterically stabilized liposomes have generated renewed interest in liposomes as drug carriers. Sterically stabilized liposomes containing doxorubicin have shown encouraging clinical activity. Immunoliposomes (ILs) represent a further strategy to enhance liposomal drug delivery, by linking liposomes to monoclonal antibodies (MAbs) directed against tumor-associated antigens. Sterically stabilized immunoliposomes directed against tumor-associated antigens have been used to target murine squamous cell lung cancer cells in vitro and in vivo and murine fibrosarcoma cells in vitro . Immunoliposomes designed for intraperitoneal therapy have been used to target human ovarian cancer cells in vitro and in ascites fluid in vivo . In addition to targeting tumor-associated an igens, immunoliposomes have been developed to target endothelial cells. Anti-HER2 immunoliposome-mediated delivery of doxorubicin may represent a particularly advantageous strategy for the treatment of breast and other cancers with frequent HER2 overexpression. Moreover, anti-HER2 immunoliposome delivery of doxorubicin provides a means of limiting the toxicity of doxorubicin in normal tissues. Immunoliposomes may prove useful as a tumor-targeted delivery system for a variety of anticancer agents, such as doxorubicin, by increasing tumor exposure and reducing toxicity to normal cells and tissues. In addition to targeted delivery of small molecule drugs, improvements in immunoliposome design and construction may lead to new therapeutic applications, such as gene therapy.

Targeting of Liposomes to Solid Tumors: The Case of Sterically Stabilized Anti-Her2 Immunoliposomes

AbstractNovel therapies for cancer call for a carrier capable of intracellular delivery of systemically administered drugs to cancer cells in solid tumors. Such carrier, sterically stabilized immunoliposomes specific to the cells expressing HER2 protooncogene (anti-HER2 SSL), was designed by conjugating Fab fragments of a recombinant humanized anti-HER2 MAb to the distal termini of poly(ethylene glycol) chains on the surface of unilamellar liposomes (size 90-100 nm) of phosphatidylcholine, cholesterol, and poly(ethylene glycol)-derivatized phosphatidylethanolamine. Anti-HER2 SSL avidly and specifically bound to cultured HER2-overexpressing cancer cells (8,000-23,000 vesicles per cell) and became endocytosed (ke=0.022–0.033 min.-1) via the coated pit pathway. Anti-HER2 SSL showed prolonged circulation lifetime in rats (blood MRT approx. 24 hours) and significantly increased antitumor activity of encapsulated doxorubicin against HER2-overexpressing human breast cancer xenografts in nude mice. Although the ...

Sterically Stabilized Immunoliposomes: Formulations for Delivery of Drugs and Genes to Tumor Cells in Vivo

Immunoliposomes represent a promising strategy to achieve targeted drug delivery for the treatment of cancers overexpressing specific surface receptors. Advances in immunoliposome design have been facilitated by independent progress in the areas of antibody-based therapeutics and liposomes, which can now be utilized for tumor-targeted drug delivery Park et al., 1997a).