Abstract
AimsTo determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation.Materials and MethodsTwo nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes’ solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intra-tumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies.ResultsNon-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin.ConclusionOptimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors.
Highlights
A main impediment of current anticancer chemotherapy is low tumor selectivity and the resultant generation of undesirable side effects [1]
Non-thermosensitive PEGylated doxorubicin liposomes (PLDs) combined with RF had the least tumor growth and the best end-point survival, better than PEGylated doxorubicin in thermosensitive liposomes (PLDTS)+RF (p,0.005) or all individual therapies (p,0.001)
At 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p,0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p,0.05); in this group the tumor has the longest exposure to doxorubicin
Summary
A main impediment of current anticancer chemotherapy is low tumor selectivity and the resultant generation of undesirable side effects [1]. Nonspecific liposomal targeting is based on the pathophysiological phenomenon characterized as the enhanced permeability and retention (EPR) effect [3]. This occurs primarily in two main pathological states: inflammation and cancer, in which particles of approximately 100 nm or less preferentially accumulate in the diseased tissues. For nano-drugs to benefit from the EPR effect, the liposomes are required to evade the immune system. This is achieved by including a lipopolymer such as PEG-DSPE in the liposome membrane [8]. A selective accumulation at the tumor site by itself is not sufficient to achieve therapeutic efficacy. There is an obligatory need for a sufficient spontaneous drug release from the liposomes in situ
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