Doxorubicin

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Doxorubicin is an anthracycline antibiotic used to treat various cancers including breast, ovarian and lung cancer. While anthracyclines are among the most effective chemotherapeutic agents in the treatment of numerous

Table 5 Advanced Formulation Strategies: Examples of Drug Products Used to Treat Cancer

Drug

Product(s)

Description

Pegylated liposomal doxorubicin Nanoparticle doxorucin

Albumin-bound paclitaxel

Liposomal cytarabine

Transdrug

Abraxane

Depocyte®

Carmustine wafer Gliadel

Surfactant-free formulation that prolongs circulation time, lowers drug distribution to healthy tissues, promoting tumor uptake Doxorubicin polyisohexylcyanoacrylate nanoparticles designed to overcome multidrug resistance caused by ABC transporters. Provides controlled release for prolonged activity Nanoparticle formulation that reduces incidence of adverse reactions and avoids need for adjuvant therapy (steroids, antihistamines) associated with surfactant formulations Depot liposomal formulation of cytarabine used as an intrathecal treatment of neoplastic and lymphomatous meningitis Wafer formulation containing carmustine that provides localized delivery of chemotherapy directly to tumor site. Wafers are implanted for removal of malignant glioma, releasing high concentrations of drug targeting microscopic tumor cells that sometimes remain after surgery malignancies, their use is limited by a dose-dependent cardiotoxicity. Over recent years, novel doxorubicin formulations have been marketed to improve therapeutic outcomes in cancer patients. These nanoscale drug delivery systems allow for optimal control over the pharmacokinetic and pharmaco-dynamic profiles of doxorubicin.

Liposomal Doxorubicin (Doxil®, Caelx)

Liposomal doxorubicin represents an advanced generation of chemotherapy delivery systems with distinct pharmacokinetic advantages and improved control of drug biodistribution. These formulations rely on Stealth® technology, where doxorubicin is encapsulated in liposomes with surface-bound PEG (i.e. pegylated liposomes, Fig. 4). As a result, the liposomes are protected from detection by the mononuclear phagocyte system. These features produce a pharmacokinetic profile of doxorubicin characterized by an extended circulation time and a reduced volume of distribution, thereby promoting tumor uptake (13,140).

Pegylated liposomes have long circulating half-lives, and are able to retain more that 90% of doxorubicin liposome-encapsulated in the plasma. This allows more time for passive targeting of drug across the leaky vasculature of the tumor. Clinical studies demonstrate a significantly lower rate of both heart failure in patients treated with liposomal-encapsulated

Novel Liposomal Herbal Drug Formulation

Figure 4 Cross-sectional view of a pegylated doxorubicin liposome. A single lipid bilayer membrane separates an internal aqueous compartment (containing drug) from the external medium. PEG molecules are engrafted onto the liposome surface to form a protective hydrophilic layer. The liposome has a mean diameter of ~85 nm. Source: From Ref. 137.

Figure 4 Cross-sectional view of a pegylated doxorubicin liposome. A single lipid bilayer membrane separates an internal aqueous compartment (containing drug) from the external medium. PEG molecules are engrafted onto the liposome surface to form a protective hydrophilic layer. The liposome has a mean diameter of ~85 nm. Source: From Ref. 137.

doxorubicin compared to doxorubicin alone. This reduced cardiotoxicity allows for administration of a larger cumulative dose of doxorubicin than what is tolerable for free doxorubicin drug (141).

Nanoparticulate Doxorubicin

Doxorubicin Transdrug® is a novel formulation of polyisohexylcyanoacry-late (PIHCA) nanoparticles containing doxorubicin. Compared to other available polymers, PIHCA shows a high efficacy/tolerance ratio in preclinical model, is produced from highly purified and characterized monomers, and the subsequent polymerization procedure is well defined and controlled. These nanoparticles are able bypass MDR mechanisms in the cancer cell, making the formulation capable of restoring the sensitivity of cancer cells to chemotherapy, overcoming resistance in cancer therapy, and thereby enhancing therapeutic outcomes in cancer treatment (142).

The mechanism through which Transdrug nanoparticles reverse MDR may involve saturation of efflux capacity of MDR transporters. This is presumably the result of the concentration gradient of drug across the cancer cell membrane that is generated by strong adsorption of the nanoparticles onto the cell surface (143-145). Doxorubicin Transdrug is undergoing clinical trials in patients hepatocellular carcinoma. These tumors are known to develop resistance to chemotherapy, so this novel formulation aims to provide preferential distribution of doxorubicin to liver and with increased efficacy by circumventing MDR (142).

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