Improved delivery of pharmaceuticals to breast cancer

Institution: University of California, San Francisco
Investigator(s): Demetrios  Papahadjopoulos , Ph.D. - Dmitri  Kirpotin , Ph.D. -
Award Cycle: 1996 (Cycle II) Grant #: 2CB-0004 Award: $145,492
Award Type: ITaMoCAs
Research Priorities
Innovative Treatments>Gene therapy and other treatments: new frontiers

This is a collaboration with: 2CB-0004A -

Initial Award Abstract (1996)
Patients with breast cancer receive drug therapy to suppress tumor growth and spread of metastasis. Major drawbacks of current anticancer drug therapies are the general toxicity of anticancer drugs and the often insufficient effect on tumors. One of the ways to improve this situation is to ensure that the injected anticancer agent is delivered mostly into the tumor tissue. In this project, we propose a novel strategy to achieve such enhanced delivery of anticancer agents to the breast cancer tumors.

Our strategy brings together two modalities. The first one is known as liposome-mediated drug delivery. The antitumor agent, prior to injection, is packed into liposomes (submicroscopic vesicles surrounded by a lipid membrane resembling that of a living cell). To make the drug-loaded liposomes invisible to the scavenger cells in the liver and spleen, which routinely remove foreign material from the blood, the surface is coated with a protective compound, polyethylene glycol. The second modality is heat treatment of the tumor. Heat treatment would substantially increase the tumor accumulation of such "sterically stabilized" liposomes, or SSL, and therefore of the SSL-carried antitumor agent. In our preliminary study, one-hour exposure of the human breast tumor grown in mice to heat increased the accumulation of SSL fourfold compared to a tumor without heat treatment.

In the proposed project, we will optimize and test the proposed two-modality strategy on an established animal model, human breast cancer tumors implanted subcutaneously in mice. First, using radioisotope-labeled SSL, we will optimize the protocol of heat treatment (temperature, duration), SSL administration, and SSL composition to achieve maximum accumulation of SSL in the heat-treated tumor. Then we will study the dynamics of SSL accumulation in heat-treated tumor and non-treated tumor. Using light microscopy and SSL labeled with colloidal gold, we will study the penetration of SSL in the tissue of heat-treated and non-treated experimental tumors. We will further use SSL bearing antibodies that recognize certain types of breast cancer cells in order to determine whether their attachment on the surface of SSL is beneficial for enhanced localization of SSL in experimental tumors. Finally, with the developed optimized protocol, we will test the efficacy of the proposed strategy for the suppression of tumor growth in the same animal model using SSL loaded with doxorubicin, a drug regularly used for breast cancer chemotherapy.

As a major result, we expect to establish the strategy of heat-enhanced delivery of SSL-carried pharmaceuticals into breast cancer tumors. This strategy will especially benefit patients with locally advanced and recurrent disease by allowing better tumor suppression with lower doses of anticancer agents, leading to fewer complications and better response to treatment. Since SSL-carried anticancer pharmaceuticals and heat treatment techniques (hyperthermia) for breast tumors are presently used in the clinic, the results of this study are likely to be quickly translated into medical practice. In the future, we plan to expand this strategy for the delivery of various agents to tumors, including other cytostatic drugs, therapeutic oligonucleotides and genes. We will also undertake necessary studies to bring the developed strategy to Phase I clinical trials.


Final Report (1998)
Our project examined the use of heat for increasing the efficacy of anticancer drug delivery to breast cancer tumors. Heating the tumor to a temperature slightly above normal (40-43 degrees C), known as hyperthermia, opens the tumor blood vessels for oxygen and anticancer drugs. We hypothesized that hyperthermia must be especially advantageous when the drug is encapsulated into liposomes, which are microscopic vesicles made of phospholipids (natural fat-like building blocks of cell membranes). Because the tumor blood vessels have larger openings than do those of normal tissue, liposomes with encapsulated drug preferentially pass from the blood into the tumor, potentially increasing drug efficacy and sparing normal tissues. Our specific aims were: to establish optimal liposome compositions, heat treatment protocols, and treatment administration sequence to achieve maximum enhancement of liposome uptake by the tumor; to study the effect of antibody-directed tumor targeting of liposomes in combination with hyperthermia on the liposome uptake by tumors; and to study the efficiency of liposome-encapsulated anticancer drugs in combination with hyperthermia for treatment of breast cancer tumors. Because our approach uses unique physiological relationships between the tumor and the living body, we studied human breast cancer tumors growing in special "nude" mice.

We found that hyperthermia increases the amount of liposomes taken up by the tumor from the blood three-fold, and established the optimum heating duration and temperature for this effect. We further found that liposomes coated with a stabilizing polymer poly(ethylene glycol) (sterically stabilized or "Stealth" liposomes) accumulate in tumors in response to heat better than "uncoated" liposomes. Importantly, we discovered that the increased uptake of liposomes by the heated tumor lasts long after the end of heat treatment. Hyperthermia increased not only the tumor uptake of liposomes, but also caused the liposomes to distribute more evenly throughout the tumor. Finally, we found that the attachment of breast cancer cell-specific antibodies to the liposomes caused additional two-fold increase in their uptake by the tumors in response to hyperthermia.

As a result of our study, and using our optimized treatment protocols, University of California, San Francisco initiated a Phase I/II trial of local hyperthermia in combination with "Stealth" liposomal anticancer drug Doxil in patients with locally advanced breast cancer. Preliminary results of this trial demonstrated that the developed treatment is safe and leads to better tumor response than chemotherapy alone.
Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors
Periodical:Pharmacological Reviews
Index Medicus: Pharm Rev
Authors: Drummond DC, Meyer O, Hong K, Kirpotin DB, Papahadjopoulos D
Yr: 1999 Vol: 51 Nbr: 4 Abs: Pg:691-743