Oncology drugs as a therapeutic class tend to have the lowest therapeutic index of any drugs in widespread clinical use, based on their antitumor efficacy vs. toxicity to the patient. Our long term objective is to employ drug carrier technology to mitigate drug toxicity, increase antitumor potency, or overcome drug physicochemical, pharmaceutical, or biodispositional shortcomings. The three main foci of our lab are to (i) develop new carrier-based formulations that have specific properties that could improve the therapeutic utility of specific drugs, (ii) investigate the mechanisms by which carrier incorporation of drugs can change the ‘apparent pharmacology’ and confer upon the drug/carrier complexes new mechanisms of antitumor effect that would not be predicted from the mechanism of action of the drug itself, and (iii) develop a rational, mechanistic, and quantitative basis upon which to combine drug carrier -based formulations with conventional cytotoxics or novel target-selective agents.
In terms of the development of new carrier-based anticancer drug formulations, our group was the first to elucidate the physicochemical basis for designing stable, liposome-based formulations containing taxanes such as paclitaxel, the active agent in Taxol®. These formulations eliminated the toxic co-solvent in which this poorly-soluble drug was administered to patients, and in addition showed significantly reduced toxicity to critical normal tissues. Our most recent publication on taxane-containing liposomes showed that in a drug-resistant, intracranial rat brain tumor model, paclitaxel showed activity superior to the clinical standard (1). Mechanistic studies that employed quantitative, systems-level modeling of antitumor pharmacodynamic effects that were observed by using magnetic resonance imaging, which provided repeated, non-invasive measurement of tumor volume progression, demonstrated that the enhanced antitumor efficacy of the liposome formulation resulted not only from its reduced toxicity, but also from a greater propensity to exert a tumor ‘priming’ effect. Other groups have shown that an initial administration of taxanes creates a defined temporal window in which a subsequent dose undergoes greater deposition. Our group demonstrated that in this drug resistant rat brain tumor model, the taxane clinical standard showed no priming effect, whereas with the liposome-based formulation, a pharmacodynamic model that hypothesized a priming effect best captured the effect of varying taxane liposome dose and schedule of administration (1).
Because of the utility of quantitative, systems-level pharmacodynamic models in creating experimentally-testable hypotheses to explain how carrier-based formulations can change the apparent pharmacology of anticancer drugs, our lab continues to explore the strengths and limitations of different types of semi-mechanistic models in terms of describing anticancer drug action quantitatively (2,3).
The necessity to acquire experimental data that enables development and testing of theses novel pharmacokinetic/pharmacodynamic models often challenges existing analytical technology. A long-standing effort of our group is to develop ultra-sensitive approaches for drug quantification in the small samples that are obtainable in animal model systems (4).
The laboratory also investigates other types of carrier-based anticancer drug formulations that have distinct properties. Our group was the first to demonstrate that an FDA-approved nanoparticulate formulation, consisting of doxorubicin encapsulated in highly-stable, long-circulating liposomes, could exert a profound ‘anti-vascular’ effect in the intracranial rat brain tumor model. When administered on a specific schedule, the doxorubicin liposome formulation compromised tumor vascular permeability, which permitted greater deposition of subsequent doses. A recent publication demonstrated that the amount of drug deposited in tumor doubled on the second administration, as a result of the vascular compromise (5). This effect is not observed with the free drug. An upcoming publication provides evidence that the nanoparticulate doxorubicin formulation exerts these novel antivascular effects by extravasation and sequestration near the tumor blood vessel wall. This creates an intra-tumor depot that kills tumor vascular endothelium over time, resulting in higher tumor perfusion and permeability of the tumor vasculature. These studies also suggest that the antivascular effect of nanoparticulate doxorubicin formulations could be exploited to increase tumor deposition of other, conventional anticancer drugs, thus overcoming the barrier of the tumor vasculature to achieving drug levels within tumors that are sufficient to reverse tumor progression.
Blanco JG. A rapid, reproducible, on-the-fly orthogonal array optimization method for targeted protein quantification by LC/MS and its application for accurate and sensitive quantification of carbonyl reductases in human liver.Analytical chemistry 2010; 82(7):2680-2689
Blanco JG. . In Rock paper scissors : how a partnership between a visionary surgeon and a newspaper publisher led to the establishment of the world's first cancer center, <[[edition]]>; <[[city]]>: Roswell Park Cancer Institute, 2011; .
Straubinger RM. Comparison of two pharmacodynamic transduction models for the analysis of tumor therapeutic responses in model systems. AAPS journal 2010; 12(1):1-10
Zhou R, Mazurchuk RV, Tamburlin JH, Harrold JM, Mager DE, Straubinger RM. Differential pharmacodynamic effects of paclitaxel formulations in an intracranial rat brain tumor model. Journal of pharmacology and experimental therapeutics 2010; 332(2):479-488
Balu-Iyer SV. Phosphatidylinositol containing lipidic particles reduces immunogenicity and catabolism of factor VIII in hemophilia a mice. AAPS journal 2010; 12(3):473-481
Ramani K, Miclea RD, Purohit VS, Mager DE, Straubinger RM, Balu-Iyer SV.Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A.Journal of pharmaceutical sciences 2008; 97(4):1386-1398
Pawaskar DK, Straubinger R, Fetterly G, Ma W, Jusko W. Physiologically based pharmacokinetic model for interactions of sorafenib and everolimus in mice. Proceedings of the American Association for Cancer Research Annual Meeting 2011; 52:Abstract #27
Trummer BJ, Iyer V, Balu-Iyer SV, O'Connor R, Straubinger RM.Physicochemical properties of epidermal growth factor receptor inhibitors and development of a nanoliposomal formulation of gefitinib. Journal of pharmaceutical sciences 2012; 101(8):2763-2776