Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.

Nanocarriers as an emerging platform for cancer therapy

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.

Liposomal drug delivery systems: from concept to clinical applications.

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

https://www.farm.ucl.ac.be/Full-texts-FARM/Danhier-2010-2.pdf

To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery

Purpose: Anti-HER2 immunoliposomes combine the tumor-targeting of certain anti-HER2 monoclonal antibodies (MAbs) with the pharmacokinetic and drug delivery capabilities of sterically stabilized liposomes. We previously showed that anti-HER2 immunoliposomes bind efficiently to and internalize in HER2-overexpressing cells in vitro , resulting in intracellular drug delivery. Experimental Design: Here we describe the pharmacokinetics and therapeutic efficacy of anti-HER2 immunoliposomes containing doxorubicin (dox) in a series of animal models. Results: Immunoliposomes displayed long circulation that was identical to that of sterically stabilized liposomes in single- and multiple-dose studies in normal rats. Anti-HER2 immunoliposome-dox produced marked therapeutic results in four different HER2-overexpressing tumor xenograft models, including growth inhibition, regression, and cures. These results demonstrated that encapsulation of dox in anti-HER2 immunoliposomes greatly increased its therapeutic index, both by increasing antitumor efficacy and by reducing systemic toxicity. Immunoliposome-dox was significantly superior to all other treatment conditions tested, including free dox, liposomal dox, and anti-HER2 MAb (trastuzumab). When compared with liposomal dox in eight separate therapy studies in HER2-overexpressing models, immunoliposome delivery produced significantly superior antitumor efficacy in each study ( P versus no cures (0 of 124) with free dox or liposomal dox. Finally, anti-HER2 immunoliposome-dox was also superior to combinations consisting of free MAb plus free dox or free MAb plus liposomal dox. Conclusions: Anti-HER2 immunoliposomes produced enhanced antitumor efficacy via targeted delivery.

/pdf/anti-her2-immunoliposomes-enhanced-efficacy-attributable-to-2rdn0wajug.pdf

Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery.

Tumor targeting using anti-her2 immunoliposomes

The human gene CC3 is a metastasis suppressor for small cell lung carcinoma (SCLC) in vivo. The ability of CC3 to impair the apoptotic resistance of tumor cells is likely to contribute to metastasis suppression. We describe here an alternatively spliced RNA of CC3, designated TC3, that encodes an unstable protein with antiapoptotic activity. TC3 and CC3 proteins share amino-terminal sequences, but TC3 has a unique short hydrophobic carboxyl terminus. Overexpression of CC3 results in massive death of rodent fibroblasts, but TC3 protects cells from CC3-induced death and from other death stimuli such as treatment with tumor necrosis factor or overexpression of Bax protein. The death-inducing activity of CC3 resides within its amino-terminal domain, which is conserved in TC3. The carboxyl terminus of TC3 is responsible for the antiapoptotic function of TC3; mutations in this domain abolish the ability of TC3 to protect cells from apoptosis. TC3 protein is short-lived due to its rapid degradation by proteasome, and it forms complexes with a regulatory subunit of proteasome known as s5α. The signal for the rapid degradation of TC3 resides within its carboxyl terminus, which is capable of conferring instability on a heterologous protein. The proapoptotic activity of CC3 in SCLC cells is induced by a wide variety of signals and involves disruption of the mitochondrial membrane potential (Δψm). The CC3 protein has sequence similarity to bacterial short-chain dehydrogenases/reductases and might represent a phylogenetically old effector of cell death similar to the recently identified apoptosis-inducing factor. CC3 and TC3 have opposing functions in apoptosis and represent a novel dual regulator of cell death.

Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis.

Novel 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 ...

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

The pharmaceutical application of liposomes has been greatly advanced over the last decade by the introduction of long-circulating liposomes,1,2 refinement of liposome preparation techniques,3 and efficient loading of drug into liposomes.4 The development of stable, long circulating liposomes has led to a new era in liposome drug delivery. For example, sterically stabilized liposomes (Doxil, Sequus Pharmaceuticals, Inc.) were generated by grafting polyethyleneglycol (PEG) onto the liposome surface. These liposomes display prolonged drug circulation and extravasate in solid tumors. However, these liposomes do not interact directly with tumor cells in vitro or in vivo, and instead they release drug for eventual diffusion into tumor cells. Similarly, progress in monoclonal antibody (mAb)-based therapy of cancer has led to clinical validation after two decades of research (reviewed in ref. 5). A leading example has been the development of mAb directed against the p185HER2 (HER2) receptor tyrosine kinase, the product of the HER2 (erbB2, neu). HER2 is highly overexpressed in a significant proportion of cancers and HER2 overexpression is clearly associated with poor prognosis in breast cancer.6 Anti–HER2 immunoliposomes were developed to combine the tumor-targeting properties of mAbs such as rhuMAbHER2 (recombinant humanized anti-HER2 monoclonal antibody) with the drug delivery properties of sterically stabilized liposomes. We previously showed that anti-HER2 immunoliposomes efficiently bind to and internalize in HER2-overexpressing cells in vitro, resulting in intracellular drug delivery.7,8 Here we show the therapeutic properties of anti-HER2 immunoliposomes containing doxorubicin (dox) in animal models (FIG.1) and the novel mechanism of intracellular drug delivery of anti-HER2 immunoliposomes in these models (FIG. 2). The antitumor efficacy of anti-HER2 immunoliposome–dox against human breast cancer xenografts was compared with control groups: saline and nontargeted liposome-dox + free rhuMAbHER2 (FIG. 1). Anti-HER2 immunoliposome-dox tested produced marked antitumor effects, including tumor growth inhibition, tumor regressions, and cures of mice and showed superior activity to the other treatment conditions.

Refaat Shalaby

Papers

Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery.

Tumor targeting using anti-her2 immunoliposomes

Alternatively spliced products CC3 and TC3 have opposing effects on apoptosis.

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

Anti-HER2 immunoliposomes for targeted drug delivery.