Selected Delivery Systems 231 Liposomes

Liposomes are perhaps the best studied vehicles in cancer drug delivery, capable of either increasing the drug concentration in solid tumors and/or limiting drug exposure to critical target sites such as bone marrow and myocardium.10'12 For example, Myocet™ is a liposomal formulation of doxorubicin (an inhibitor of topoisomerase II) approximately 190 nm in size that was approved by the European Agency for the Evaluation of Medicinal Products (EMEA) in 2000 for the treatment of metastatic breast cancer. This formulation provides a limited degree of prolonged circulation when compared with doxorubicin in the free form. Myocet™ releases more than half of its associated doxorubicin within a few hours of administration and 90% within 24 h. Similar to intravenously injected nanoparticulate systems, liposomes are rapidly intercepted by macrophages of the reticuloendothelial system.10 Hepatic deposition of Myocet™ could lead to gradual release of the cytotoxic agent back to the systemic circulation (a macrophage depot system), as well as induction of Kupffer cell apoptosis.10 Following apoptosis, restoration of Kupffer cells may take up to two weeks.13 A potentially harmful effect is the occurrence of bacteriemia during the period of Kupffer cell deficiency. Although Myocet™ administration decreases the frequency of cardiotoxi-city and neutropenia compared with free drug,14 there is still controversy as to whether liposomal encapsulation exhibits equivalent efficacy to doxorubicin.15

Macrophage deposition of intravenously administered liposomes can be markedly minimized either by bilayer or surface modification.10,16 Regulatory approved examples include DaunoXome®, a daunorubicin-encapsulated liposome 45 nm in size with a rigid bilayer for HIV-related Kaposi's sarcoma, and Doxil®/Caelyx®, a poly(ethylene glycol)-grafted rigid vesicle of 100-nm diameter with encapsulated doxorubicin for HIV-related Kaposi's sarcoma and refractory ovarian carcinoma. As a result of their small size, rigid bilayer, and hydrophilic surface display (as in the case of Doxil®), these formulations exhibit poor surface opsonization, a process that limits vesicle recognition by macrophages in contact with the blood and consequently prolongs their residency time within the vasculature.10,16 For instance, Doxil® has a biphasic circulation half-life of 84 min and 46 h in humans. In addition, Doxil® also has a high drug loading capacity; here doxorubicin is loaded actively by an ammonium sulfate gradient (as doxorubicin sulfate) yielding liposomes with a high content of doxorubicin aggregates, which remain highly stable within the vasculature with minimum drug loss.17 Therefore, it is not surprising to see that such liposomal formulations exhibit favorable pharmacokinetics when compared with the free drug. For example, the area under the curve after a dose of 50 mg/m2 doxorubicin encapsulated in long-circulating liposomes is approximately 300-fold greater than that of free doxorubicin.17 In addition, clearance and volume of distribution are reduced by at least 250- and 60-fold, respectively.17 However, as a result of their prolonged circulation times, alternative toxic reactions have been reported with such vehicles. The most notable dose-limiting toxicity associated with continuous infusion of Doxil® is palmar-plantar erythrodysesthesis.17

Following extravasation into solid tumors, long-circulating liposomes often distribute heteroge-neously in perivascular clusters that do not move significantly and poorly interact with cancer cells.18 Therefore, the efflux of drug must follow the process of liposome extravasation at a rate that maintains free drug levels in the therapeutic range. The rate of drug release from liposomes not only depends on the composition of the interstitial fluid surrounding tumors but also on the drug type and encapsulation procedures. The importance of the latter is highlighted by the observation that extravasated long-circulating cisplatin-containing liposomes (where cisplatin is loaded passively) lack anti-tumor activity, whereas cisplatin in free form is capable of inserting cytotoxicity.19 This is in contrast to the effective anti-tumor property of the same liposomal lipid composition containing entrapped doxor-ubicin. It is believed that nonspecific chemical disruption or collapse of the liposomal pH gradient, that is used to load liposomes actively with doxorubicin, may trigger doxorubicin release.17

Long-circulating liposomes have the capability to deliver between 3 and 10 times more drug to solid tumors compared with the administered drug in its free form. If the entrapped drugs are released from extravasated liposomes, it is very likely that these vesicles inherently overcome a certain degree of multidrug resistance by the tumor cells. Thus, tumor regression is to be expected with tumors exhibiting a low resistance factor. With tumors exhibiting higher resistance levels, due to over-expression of energy-dependent efflux pumps such as P-glycoprotein and multidrug-resistance-related protein, alternative approaches are necessary. One effective strategy is to use long-circulating temperature-sensitive liposomes in conjugation with hyperthermia, but this approach has limited applicability for visceral and widespread malignancies.20 Others have elaborated on biochemical triggers such as cleaveable poly(ethylene glycol)-phospholipid conjugates to generate fusion competent vesicles21 and enzyme-mediated liposome destabilization and pore formation.22-24 Examples of the latter include long-circulating liposomes with attached protease-sensitive haemolysin22 and pro-drug ether liposomes (e.g., vesicles containing phospholipids with a nonhydrolyzable ether bond in the 1-position), which are susceptible to degradation by secretory phospholipases.23,24 For instance, the level of secretory phospholipases (such as the secretory phospholipase A2) is dramatically elevated within the interstitium of various tumors. Secretory phospholiapse A2 not only acts as a trigger resulting in the release of encapsulated cytotoxic drugs from pro-drug ether liposomes, but also generates highly cytotoxic lysolipids that destabilizes plasma membrane of tumor cells, thereby enhancing their permeability to cyto-toxic drugs.24

There are several approaches that exploit active targeting of long-circulating liposomes to tumor cells, where receptor-mediated internalization is strongly believed to bypass tumor cell multidrug-efflux pumps.10,16,17,25 These strategies utilize tumor-specific monoclonal antibodies or their internalizing epitopes, or ligands, such as folic acid, which are attached to the distal end of the poly(ethylene glycol) chains expressed on the surface of long-circulating liposomes. Nevertheless, with such approaches the delivery part is still passive and relies on liposome extravasation.

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