By Yannan (Nancy) Dou and Christine Allen
Liposomes are one of the few nanotechnologies that have resulted in approved products for clinical use in oncology (e.g., Myocet, Doxil, DaunoXome). Despite this success, there are challenges associated with this delivery technology that limit the therapeutic effect of the liposome-based formulations. These challenges include variability in tumor accumulation of the nanotechnology due to clinical heterogeneity in the enhanced permeability and retention (EPR) effect, poor tumor penetration of the carrier, and limited drug release once at the tumor site. Thermosensitive liposomes have the potential to overcome these obstacles by providing triggered drug release under conditions of mild hyperthermia. The thermosensitive liposomes can be designed to largely provide intravascular drug release, eliminating reliance on the EPR effect, or to release the drug following extravasation into the tumor interstitium.
Pioneering work by Dewhirst and Needham has resulted in a thermosensitive liposome formulation of doxorubicin known as ThermoDox (Celsion Corporation), which is now in clinical development. Phase 3 results highlight that the selection of the optimal heating protocol is essential to the success of thermosensitive liposome-based drug delivery strategies.
Cisplatin is another drug that has been encapsulated in liposomes (i.e., SPI-77) and found to yield unimpressive efficacy results clinically, due in large part to lack of drug release from the delivery system. In our abstract, being presented at the 2015 National Biotechnology Conference, we describe the in vivo therapeutic efficacy obtained with our recently developed cisplatin-encapsulating thermosensitive liposome formulation (referred to as HTLC) in various cervical tumor xenograft models, including SiHa, ME-180, and patient-derived (PDX).
In these studies, local heating of the tumor area was achieved using a custom-designed laser-based heating setup with real-time temperature feedback and adjustment based on a point source. In brief, we observed significantly greater in vivo response in the SiHa model in comparison to the ME-180 model following treatment with HTLC combined with local heating of the tumors to 42°C. This is in contrast to in vitro data showing that ME-180 cells are more sensitive to cisplatin than SiHa cells. Quantitative ex vivo analysis of tumor microenvironment parameters showed that ME-180 tumors have significantly larger areas of hypoxia and higher stromal content than SiHa tumors, both of which are well-known barriers to drug delivery.
To extend our efforts, the therapeutic efficacy of HTLC was also examined in several more clinically relevant cervical PDX models. In these studies, we observed significant inter-model (i.e., among PDX models) and intra-model (i.e., within the same PDX model) differences in treatment response. The intra-model differences may be due to factors such as variations in tumor uptake of the drug and heterogeneity in temperature distribution within the heated tumors. On the other hand, based on our results in the SiHa and ME-180 models, we hypothesize that the inter-model differences are mainly due to variations in tumor microenvironment among the different models, such as degree of hypoxia and stromal content. We are currently in the process of further analysis to validate this hypothesis.
Thus, overall these studies employ thermosensitive drug delivery as a means to address the challenge of limited drug availability from liposome systems once at the tumor site. Although our HTLC formulation in combination with heating resulted in significant improvements in therapeutic efficacy in comparison to free drugs in various tumor models, substantial variability in response was observed among the distinct models and within each tumor model. This highlights the impact of heterogeneity in cancer on therapeutic response. Further studies on the influence of the tumor microenvironment on the therapeutic effect of thermosensitive liposomes are necessary for implementation of personalized approaches that yield significant improvements in treatment outcomes for cancer patients.