CT-2106 is a 20(S)-camptothecin poly-L-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.
CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.
Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.
CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.
[Show abstract][Hide abstract] ABSTRACT: Nanoparticle (NP) drug delivery systems (5-250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, delaying opsonization, and increasing the extent of tissue specific accumulation.
[Show abstract][Hide abstract] ABSTRACT: Cytotoxic chemotherapeutic agents are the mainstay of anti-cancer therapy. Improvements in the therapeutic ratio of cytotoxic
anti-cancer drugs remain a major unmet need as these agents are limited by toxicity to normal organs and relatively modest
anti-tumor efficacy as a result of lack of specificity. Cytotoxic drugs target rapidly dividing cells in normal tissues with
similar effects to those in tumor tissue. One approach to overcoming these deficiencies is to chemically conjugate cytotoxic
molecules such as paclitaxel to a macromolecular carrier. This creates new chemical entities that enhance distribution to
tumor tissues, render hydrophobic agents water soluble, potentially decrease toxicity to normal organs, and enhance efficacy.
Our group has focused on covalently linking cytotoxic agents to a macromolecular peptide polymer, poly-l-glutamic acid (PGA). PGA was selected for its large number of potential binding sites, high aqueous solubility, lack of immunogenicity,
and its biodegradability. This chapter focuses on the developmental challenges associated with polymer therapeutics, using
as an example, CT-2103, generically named paclitaxel poliglumex. Sections are devoted to chemistry, manufacturing, and controls
specifically addressing development of characterization methods and release specifications for this complex molecule; preclinical
pharmacology and toxicology; pharmacokinetics and metabolism including an interaction with estradiol; and clinical development
through Phase III trials. A brief review of a second PGA conjugate with camptothecin, CT-2106, is also included.
[Show abstract][Hide abstract] ABSTRACT: Polymeric nanoparticulate systems have garnered wide interest as vehicles for intracellular reporter agents and anti-cancer drugs, in anti-cancer gene therapy, and in reducing the adverse toxic effects of metal nanoparticles. These wide ranging applications have been possible due to a favourable blend of polymer properties such as facile chemistry, diverse synthesis options, and amenability towards functionalization. An array of polymeric nanosystems have been developed which exhibit better encapsulation, higher bioavailability, and controlled release of therapeutic agents. In this review, we discuss strategies for synthesizing, tailoring and targeting polymeric nanoparticles, schemes for reducing metal nanoparticle toxicity by using polymers, and recent aspects of internalization and biodistribution of nanoparticulate systems with reference to cancer. We also present the recent clinical status of certain key nanoparticulate anti-cancer drug and gene formulations.
Proceedings of the National Academy of Sciences, India - Section B: Biological Sciences 10/2012; 82(1). DOI:10.1007/s40011-012-0075-4 · 0.40 Impact Factor
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