Monoclonal antibody exposure in rat and cynomolgus monkey cerebrospinal fluid following systemic administration.

BACKGROUND: Many studies have focused on the challenges of small molecule uptake across the blood-brain barrier, whereas few in-depth studies have assessed the challenges with the uptake of antibodies into the central nervous system (CNS). In drug development, cerebrospinal fluid (CSF) sampling is routinely used as a surrogate for assessing CNS drug exposure and biomarker levels. In this report, we have studied the kinetic correlation between CSF and serum drug concentration-time profiles for five humanized monoclonal antibodies in rats and cynomolgus monkeys and analyzed factors that affect their CSF exposure. RESULTS: Upon intravenous (IV) bolus injection, antibodies entered the CNS slowly and reached maximum CSF concentration ( CSF T max ) in one to several days in both rats and monkeys. Antibody serum and CSF concentration-time curves converged until they became parallel after CSF T max was reached. Antibody half-lives in CSF ( CSF t ½ ) approximated their serum half-lives ( serum t ½ ). Although the intended targets of these antibodies were different, the steady-state CSF to serum concentration ratios were similar at 0.1-0.2% in both species. Independent of antibody target and serum concentration, CSF-to-serum concentration ratios for individual monkeys ranged by up to tenfold from 0.03 to 0.3%. CONCLUSION: Upon systemic administration, average antibodies CSF-to-serum concentration ratios in rats and monkeys were 0.1-0.2%. The CSF t ½ of the antibodies was largely determined by their long systemic t ½ ( systemic t ½ ).

Conjugation of bevacizumab to cationic liposomes enhances their tumor-targeting potential.

AIMS: Cationic liposomes have been shown to preferentially target the tumor vasculature, but not uniformly. Bevacizumab antibody selectively accumulates in tumors expressing VEGF. We thus developed bevacizumab-modified, pegylated cationic liposomes (PCLs) to improve the distribution of liposomes along tumor vessels, and to enhance tumor targeting. MATERIALS & METHODS: We evaluated the delivery vehicle both in the absence and presence of VEGF, using human pancreatic cancer (Capan-1, HPAF-II and PANC-1) and endothelial (MS1-VEGF and HMEC-1) cell lines. RESULTS: All cell lines except for HMEC-1 secreted VEGF. Modification of PCLs with bevacizumab did not alter zeta-potential, but increased overall liposome size. The toxicity profile for bevacizumab-modified PCLs was cell line dependent and, in general, bevacizumab improved cellular uptake and tumor targeting of PCLs. CONCLUSION: Bevacizumab-modified PCLs represent a potential improvement over the unmodified variety, supporting their future development for the treatment of cancer.

Fighting cancer: from the bench to bedside using second generation cationic liposomal therapeutics.

The use of second generation cationic liposomes to deliver cytotoxic drugs to solid tumors is a rational and promising therapeutic approach, given the natural affinity of cationic carrier molecules for the tumor microvasculature. Cationic liposomal therapeutics are effective in the treatment of cancers that are resistant to conventional chemotherapy and other treatment modalities. Researchers are now exploring novel ways to combine cationic nanosystems with other treatment approaches. For example, strategies for using cationic liposomes with hyperthermia or magnetic fields have been evaluated. Drug-loaded cationic liposomes have been documented to induce tumor vascular defects, alter vascular function and limit the growth of the primary tumors and metastasis. In this review, we discuss general features of the endothelium as a function of its tissue environment. We discuss the rationale for targeting tumor vessels over the tumor interstitial matrix, and for the development of second generation cationic lipids and liposomes for tumor vascular targeting. We evaluate the benefits of incorporating the polymer polyethylene-glycol (PEG) in conventional and cationic liposomes for nonspecific and relatively vascular-specific tumor targeting, respectively. Finally, we review preclinical and clinical investigations evaluating drug-loaded cationic liposomes in cancer treatment.

Importance of the liposomal cationic lipid content and type in tumor vascular targeting: physicochemical characterization and in vitro studies using human primary and transformed endothelial cells.

Using cationic liposomes to deliver cytotoxic molecules to the tumor microvasculature is currently being developed for the treatment of cancer and other angiogenesis-related diseases. To improve on their beneficial properties, the authors have examined whether the particular cationic lipid type and lipid content employed are important factors influencing cellular interactions and formulation effects. The authors prepared different PEG (polyethylene glycol)-modified cationic liposomes (PCLs) with varying percent cationic lipid content and lipid type, and evaluated liposome size, surface charge (zeta) potential, and cellular properties in vitro. The cell lines used were human umbilical vein (HUVEC), lung microvascular (HMVEC-L and HPVE-26), coronary microvascular (HMVEC-C), dermal microvascular (HMVEC-D), and immortalized dermal microvascular (HMEC-1) endothelial cells. In vitro experiments consisted of cellular uptake and cytotoxicity studies, fluorescence-activated cell sorting (FACS) analysis, fluorescence, and transmission electron microscopic analysis. Liposome size and zeta potential analysis of five different PCLs revealed significant differences in their physicochemical properties. Some cationic lipids formed relatively toxic liposomes compared to others. The efficiency of loading chemotherapeutic drugs (doxorubicin hydrochloride, etoposide), affinity of PCLs for endothelial cells, and formulation effects varied according to cationic lipid content and the lipid type. Cellular uptake was observed in lung, dermal, and coronary endothelial cells. Heparan sulfate proteoglycans were found present on HMEC-1 cells, which may have enabled PCL uptake. In conclusion, physicochemical properties of cationic liposomes and their ability to interact with endothelial cells are important factors to consider during the early stages of formulation development for the treatment of cancer and other angiogenesis-dependent diseases.