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Background Nanoscale drug delivery systems accumulate in solid tumors preferentially by the enhanced permeation and retention effect (EPR-effect). Nevertheless, only a miniscule fraction of a given dosage reaches the tumor, while >90% of the given drug ends up in otherwise healthy tissues, leading to the severe toxic reactions observed during chemotherapy. Once accumulation in the tumor has reached its maximum, extracorporeal elimination of circulating nanoparticles by plasmapheresis can diminish toxicities. Objective In this study, we investigated the effect of dosing and plasmapheresis timing on adverse events and antitumor efficacy in a syngeneic rat tumor model. Methods MAT-B-III cells transfected with a luciferase reporter plasmid were inoculated into female Fisher rats, and pegylated liposomal doxorubicin (PLD) was used for treatment. Plasmapheresis was performed in a discontinuous manner via centrifugation and subsequent filtration of isolated plasma. Results Bioluminescence measurements of tumor growth could not substitute caliper measurements of tumor size. In the control group, raising the dosage above 9 mg PLD/kg body weight did not increase therapeutic efficacy in our fully immunocompetent animal model. Plasmapheresis was best done 36 h after injecting PLD, leading to similar antitumor efficacy with significantly less toxicity. Plasmapheresis 24 h after injection interfered with therapeutic efficacy, while plasmapheresis after 48 h led to fewer side effects but also to increased weight loss. Conclusion Long-circulating nanoparticles offer the unique possibility to eliminate the excess of circulating particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely toxicity-related therapeutic limitations.

Nanoparticle-based drug delivery to ease anticancer therapy relies primarily on the enhanced permeability and retention effect (EPR). The leaky vascular structure in tumors allows extravasation of nanoparticles, often termed passive targeting. Long term retention of nanoparticles is attributed to the lack of lymphatic drainage, and unidirectional extravasation has been implied.Fluorescent liposomes with a plasma half-life of 29h were injected into tumor-bearing rats, and biodistribution in tumor, skin, paws and ears was monitored via in vivo fluorescence measurements. To calculate tissue accumulation, an algorithm was developed to subtract the blood signal from the total fluorescence recorded. Accumulation in tumor tissue was much higher than that in other tissues monitored, initially exhibiting very rapid accumulation followed by a long plateau phase with little change. Discontinuous plasmapheresis was established that was as effective as highly sophisticated clinical plasmapheresis. We observed no difference in the tumor tissue's accumulation when plasmapheresis was performed 22h after liposome injection. In contrast, plasmapheresis led to a significant inhibition of further accumulation in other tissues. When the liposomes' blood concentration was rapidly lowered, we detected no drop in tumor fluorescence. Thus extravasation via EPR is most likely a route of no return. These data support the emerging view of a more dynamic model of EPR, where gaps or entire vessels may open and close over time, or accumulated liposomes become entangled within the pores, hampering further accumulation.

According to early experiments with natural extracts, phosphatidylcholines (PCs) are widely considered essentially non-toxic. In addition to these physiological mixed-chain PCs, many different synthetic diacyl-PCs are currently available, but they have never been systematically evaluated for any interference with cell proliferation. We thus investigated the cell proliferation of several cell lines in the presence of various liposomes consisting of a single PC component and cholesterol.Most of the PCs investigated did not interfere with cell proliferation, supporting the notion that most PCs are safe excipients. Significant IC50 values below 0.5mM were detected for PC(12:0/12:0), PC(14:1/14:1)trans and all diacyl-PCs containing two polyunsaturated fatty acids (PUFAs). The ω-3 PC(22:6/22:6) was the most toxic PC assessed, revealing IC50 values below 100μM, but no rule concerning ω-3/6 configuration or acyl chain length could be observed. Physiological mixed-chain PCs containing PUFAs were much less toxic than respective non-physiological diacyl-PCs. All trans fatty acids in diacyl-PCs interfered more with proliferation than their respective cis-configured counterparts. Depending on the concentration, those diacyl-PCs not only inhibited proliferation but also induced cell death.Unlike the non-toxic PCs usually used for liposomal drug delivery, the elucidated diacyl-PCs may be worthy of further examination to eventually construct a toxic shell for toxic drugs, thereby enhancing anticancer drug delivery via lipid particles.