Targeted liposomes against melanoma

We previously showed that targeted liposomes having an antibody against TROY, a very specific surface receptor of melanoma cells can successfully be taken up by A375 melanoma cells as compared to control liposomes lacking this antibody, but now we did not have any preliminary data that showed that this system could work in vivo as well, which is the ultimate goal. We now recently discovered that Doxorubicin (DOX)-loaded, pegylated liposomes having an Fab antibody against TROY covalently attached to the PEG molecules on the surface of the liposomes significantly reduced melanoma growth in a nude mouse xenograft model compared to control, non-targeted counterparts.

Liposomal targeting to reduce the side effects of chemotherapy

The lack of tumor specificity remains a major drawback for effective chemotherapies and results in dose-limiting toxicities. However, a ligand-mediated drug delivery system should be able to render chemotherapy more specific to tumor cells and less toxic to normal tissues.  

Doxyl (R) a Doxorubicin (R) liposomal formulation is prescribed for ovarian cancer but displays high toxicities. Companies are trying to modify this liposomal formulation by incorporating a targeting moiety such as an antibody to epidermal growth factor receptor (EGFR) which is highly expressed in ovarian cancer cells. So far, this strategy has failed, maybe as a result of the steric hindrance of the immobilized antibody on the surface of the stealth liposomes. Novel formulation strategies are needed to make more effective  targeting liposomes if we are to reduce the side-effects of chemotherapy. 

How formulation strategy could impact drug toxicity.

The incidence of malignant melanoma of the skin, the most serious form of skin cancer, is increasing faster than that of any other cancer in the United States. Chemoprevention as a strategy for the management of malignant melanoma entails the use of specific agents to block, reverse, or suppress carcinogenesis and thereby prevent the development of primary or secondary cancers. Retinoids are among the most promising chemopreventive agents with clinical effects of retinoid chemoprevention having been demonstrated in cancers of the head and neck, lung, cervix, ovaries, and skin.

However, topical tretinoin (ATRA) induces moderate to severe skin irritation in 90% of patients and was the main reason for discontinuation of treatment for almost 50% of patients. This high incidence of irritation, leading to poor compliance, has precluded its use. Irritation has been attributed, in part, by an overload of the ATRA-dependent pathways with nonphysiologic amounts of exogenous ATRA in the skin. A topical sustained delivery system might prevent this overload, thus reducing skin irritation, making topical ATRA therapy a viable chemopreventive agent. Natural or synthetic polymers that are biodegradable may offer advantages over nonbiodegradable polymers for topical drug delivery applications.

A biodegradable polymer would be advantageous for topical drug delivery. Chitosan (CH) is a fully biodegradable natural cationic biopolymer which has good skin substantivity and can slow the release of active substances such as ATRA. In addition, there is a history of using chitosan for drug delivery applications.

The in vitro studies showed that CH gels act as sustained delivery vehicles for ATRA, the delivery rate being a function of the viscosity of the gel. The cumulative percutaneous penetration of ATRA could be decreased from 70% to 10% by increasing the viscosity of the topical CH gel. The preliminary clinical studies indicated a minimal erythema in all formulations, including the control gel, without significant difference in irritation or adverse reactions between the gel formulations. Thus, CH gels may offer some advantages over existing topical delivery systems for the administration of irritating substances, such as ATRA for the chemoprevention of skin cancers.

Ask the complete study at http://www.biovolutions.com/contactus.htm

 I also found that in vitro models are an inexpensive way to weed-out ineffective formulations and provide preliminary evidence of safety and efficacy of a drug product. A case in point: we have recently tested a topical formulation which claimed to offer enhanced penetration of a Case 3 molecules (Case 3 as defined by the Biopharmaceutics Classification System (BCS) as a molecule which has high solubility but poor penetration). A quick analysis using our in vitro assay determined that the formulation did not enhance the penetration of this molecule across human skin. The in vitro assay test led to a series of iterative steps toward a more penetrating formulation which did not exhibit skin toxicity according to the Epiderm 200 toxicity test from MatTek, another in vitro assay that helps us optimize our formulations. As you can see, by combining in vitro efficacy models with in vitro toxicity models we were able to rapidly screen out problem formulations and arrive at an optimum formulation. 

Why the formulation is strategic ?

Since I launched BioVolutions (http://www.biovolutions.com/) 18 months ago, I have realized that formulation development was often overlooked as a strategic development phase in the product life cycle. However, either for biotech companies or large pharmaceutical group, formulation development is the best way to accelerate, protect or improve revenue streams.

In summary, a good formulation development program is critical and I will use this blog to share my experience with you and to make the formulation an integral part of your product life cycle.

Best