Using highly efficient intraliposomal trapping agents, small molecule drugs can be stably encapsulated in the liposome interior resulting in long circulation lifetimes, sustained drug exposure at the site of the tumor, and an increased capacity for molecular targeting using antibodies specific for cell surface receptors overexpressed preferentially on cancer cells. Here we provide examples of two clinical stage drugs, a nontargeted nanoliposomal CPT-11 (MM-398) and an ErbB2(F5)-targeted pegylated liposomal doxorubicin (F5-PLD or MM-302), including their therapeutic design, preclinical rationale, and current clinical status.  F5-PLD has recently completed Phase I trials as a monotherapy in ErbB2-overexpressing breast cancer and relies on tumor cell internalization of the targeted cytotoxic to significantly improve drug delivery and therapeutic activity.  Nanoliposomal CPT-11 is currently in Phase III trials for pancreatic cancer and displays a slow-release rate in the circulation (T1/2=56.4 h) that results in tumor-specific conversion of the inactive CPT-11 prodrug to the 1000-times more active SN-38 metabolite by tumor associated macrophages.  The result is long duration sustained exposure to the active metabolite compared to treatment with the unencapsulated or free form of the drug.  Phase II studies in gastric, colorectal, and pancreatic cancers are either enrolling or have recently been completed.  We also describe some novel modes of administration or uses of the technology, such as convection enhanced delivery (CED) to bypass the blood brain barrier and increase the exposure of drug in the brain while minimizing systemic exposure.

Development of lipid-based nanotherapeutics for treating solid tumors

246th National Meeting (2013)

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