Doxil®--the first FDA-approved nano-drug: lessons learned.

The rapid recognition of intravenously injected colloidal carriers, such as liposomes and polymeric nanospheres from the blood by Kupffer cells, has initiated a surge of development for "Kupffer cell-evading" or long-circulating particles. Such carriers have applications in vascular drug delivery and release, site-specific targeting (passive as well as active targeting), as well as transfusion medicine. In this article we have critically reviewed and assessed the rational approaches in the design as well as the biological performance of such constructs. For engineering and design of long-circulating carriers, we have taken a lead from nature. Here, we have explored the surface mechanisms, which affords red blood cells long-circulatory lives and the ability of specific microorganisms to evade macrophage recognition. Our analysis is then centered where such strategies have been translated and fabricated to design a wide range of particulate carriers (e.g., nanospheres, liposomes, micelles, oil-in-water emulsions) with prolonged circulation and/or target specificity. With regard to the targeting issues, attention is particularly focused on the importance of physiological barriers and disease states.

Long-Circulating and Target-Specific Nanoparticles: Theory to Practice

There are many potential barriers to the effective delivery of a drug in its active form to solid tumors. Most small-molecule chemotherapeutic agents have a large volume of distribution on i.v. administration ([Speth et al., 1988][1]; [Chabner and Longo, 1996][2]). The result of this is often a

Optimizing Liposomes for Delivery of Chemotherapeutic Agents to Solid Tumors

Inflammation is a fundamental protective response that sometimes goes awry and becomes a major cofactor in the pathogenesis of many chronic human diseases, including cancer. Here we review the evolutionary relationship and opposing functions of the transcription factor NF-κB in inflammation and cancer. Although it seems to fulfill a distinctly tumor-promoting role in many types of cancer, NF-κB has a confounding role in certain tumors. Understanding the activity and function of NF-κB in the context of tumorigenesis is critical for its successful taming, an important challenge for modern cancer biology.

Inflammation meets cancer, with NF-κB as the matchmaker

Advanced strategies in liposomal cancer therapy: problems and prospects of active and tumor specific drug release.

Here, we investigate various factors affecting the therapeutic efficacy of free doxorubicin (Free-Dox) and polyethylene glycol (PEG)-coated (PEGylated) liposomal doxorubicin (referred to as Doxil) in the ascitic J6456 lymphoma model of BALB/c mice. Free drug and liposomal drug were affected differently by the tumor burden and route of treatment administration. A delay in start of treatment from day 1 to day 5 almost completely abolished the efficacy of Free-Dox, whereas that of Doxil was only minimally reduced. Contrasting effects on the therapeutic efficacy of Free-Dox and Doxil were obtained by changing treatment administration from the i.v. to the i.p. route; the efficacy of free drug was relatively enhanced, whereas that of liposomal drug was relatively diminished. Overall, Doxil given by the systemic i.v. route was the most effective treatment in prolonging median survival and obtaining cures. Variations in the dose-schedule treatment regime confirm the superior therapeutic profile and reduced dependence on tumor burden of the PEGylated liposomal formulation over free drug. In addition, these experiments indicate that, at equal dose intensity, the dose level is more important than the frequency of administration for therapeutic activity.

https://clincancerres.aacrjournals.org/content/clincanres/4/2/499.full.pdf

Comparative study of the antitumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model.

Polyethylene glycol-coated liposomal doxorubicin (Doxil) has a sustained release profile and a mild myelosuppressive effect that may enable a beneficial interaction with lymphocyte-activating cytokines, such as interleukin 2 (IL-2). Previous studies have shown that liposome entrapment of IL-2 potentiates its immunomodulatory effects and reduces the need for frequent dosing. We assessed the therapeutic effect of Doxil (8 mg/kg) followed by free or liposomal IL-2 (50,000 Cetus Units ×3) in mice bearing M109 lung adenocarcinoma transplanted i.v. or i.p. Doxil was always administered i.v., whereas IL-2 was given i.v. in the i.v. M109 model and i.p. in the i.p. M109 model. The optimal combined treatment was significantly more effective than liposomal chemotherapy alone, producing tumor-free, long-term survivors in 100% (i.v. M109) and 94% (i.p. M109) of the mice, compared with 50% and 56%, respectively, for Doxil alone. The efficacy boost of IL-2 appeared to be formulation dependent, with free IL-2 and IL-2 in small unilamellar vesicles most active in the i.v. tumor model, and IL-2 in multilamellar vesicles most active in the i.p. tumor model. The combination of Doxil with free or liposomal IL-2 was devoid of any conspicuous toxicity. Cytokine treatment without chemotherapy was completely ineffective. Liposome-based chemoimmunotherapy is a synergistic and highly efficacious approach to eradicate metastatic and regionally spread tumors.

https://clincancerres.aacrjournals.org/content/clincanres/5/3/687.full.pdf

Enhancement of Antitumor Activity of Polyethylene Glycol-coated Liposomal Doxorubicin with Soluble and Liposomal Interleukin 2

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Comparative study of the antitumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model.

Enhancement of Antitumor Activity of Polyethylene Glycol-coated Liposomal Doxorubicin with Soluble and Liposomal Interleukin 2