Macromolecular Drug Delivery Systems Research Articles

Biodistribution of doxorubicin-alkylated poly( l-lysine citramide imide) conjugates in an experimental model of peritoneal carcinomatosis after intraperitoneal administration

Peritoneal spread is a common manifestation in ovarian and gastrointestinal cancer. Intraperitoneal (i.p.) chemotherapy after cytoreductive surgery is associated with high systemic or local toxicity. A macromolecular drug delivery system was evaluated with the aim of improving the therapeutic index of i.p. chemotherapy. Peritoneal carcinomatosis was generated in BDIX rats ( n = 55) by i.p. injection of 2 million DHDK12 cells. Fourteen days later, doxorubicin (DOX) and two DOX-alkylated poly( l-lysine citramide imide) conjugates bearing 9.5% and 20.5% (w/w) chemically bound drug, respectively, were given i.p. to rats at a single 2 mg DOX/kg dose. Free and polymer-bound DOX were assessed in plasma, peritoneal fluid, abdominal tissues and heart, 15 min, 2, 6, 24, 48 and 168 h after injection. According to pharmacokinetic profiles, the peritoneal fluid areas under the concentration versus time curves (AUCs) were 2 and 2.6 times greater for the conjugates (P-DOX20 and P-DOX10, respectively) than for the free drug, respectively. Conjugates crossed the peritoneal barrier slower than the free drug. For the tumor, AUCs were, respectively, 3 and 7 times higher for the conjugates than for free DOX. The elimination half-lives of the conjugates were higher than that calculated for the free drug. Only very small concentrations were detected in peripheral organs and in the heart. In contrast, significant retention and accumulation of the conjugates were found in abdominal organs, particularly in the tumor. There was no sign of macroscopic chemical peritonitis after injection of the polymer–DOX conjugates. In conclusion, the conjugates have higher elimination half-lives than free DOX and were preferentially retained in abdominal organs and in the peritoneal carcinomatosis. This feature is of clinical interest to target tumor deposits.

Enhancing the Site-Specific Targeting of Macromolecular Anticancer Drug Delivery Systems

The application of macromolecules as vehicles for anticancer drug delivery is a burgeoning field of interest. One of the hallmarks of using such systems, however, is that they must be capable of site-specific drug delivery. As such, augmenting the targeting of drug delivery systems to specified sites is paramount. To date, a number of synthetic strategies have been utilized to introduce targeting moieties to macromolecular drug delivery systems to enhance specific targeting. This scheme frequently involves the introduction of some type of biologically recognizable marker to the delivery system. Biological evaluations have substantiated the rationale that introducing targeting groups can significantly increase specificity. This concise review will attempt to encompass what strategies have been done to increase the specificity of macromolecular anticancer drug delivery systems along with their biological activities.

Polymeric anticancer drugs with pH-controlled activation

Use of macromolecular water-soluble carriers of anti-cancer drugs represents a promising approach to cancer therapy. Release of drugs from the carrier system is a prerequisite for therapeutic activity of most macromolecular anti-cancer conjugates. Incorporation of acid-sensitive spacers between the drug and carrier enables release of an active drug from the carrier in a tumor tissue, either in slightly acidic extracellular fluids or, after endocytosis, in endosomes or lysosomes of cancer cells. This paper reviews advances in development and study of properties of various acid-sensitive macromolecular drug delivery systems, starting from simple polymer–drug conjugates to ending with site-specific antibody-targeted polymer–drug conjugates.

Polymeric micelle drug carrier systems: PEG-PAsp(Dox) and second generation of micellar drugs.

Polymeric micelles are one of the most refined and promising modalities of macromolecular drug delivery systems , and show unique disposition characteristics in the body suitable for the drug targeting (e.g., prolonged blood circulation and significant tumor accumulation as described in earlier chapter) . Like the other promising modalities (i.e., watersoluble polymers and long-circulating liposomes), the polymeric micelle carrier systems might possess several advantages such as (1) the applicability to a variety of therapeutic agents (e.g., hydrophobic compounds, metal complexes and charged macromolecules such as polypeptides and nucleic acids), (2) unnecessariness of chemical structure

Cancer-targeted polymeric drugs.

A major challenge in cancer chemotherapy is the selective delivery of small molecule anti cancer agents to tumor cells. Water-soluble polymer-drug conjugates exhibit good water solubility, increased half-life, and potent anti tumor effects. By localizing the drug at the desired site of action, macromolecular therapeutics have improved efficacy and enhanced safety at lower doses. Since small molecule drugs and macromolecular drugs enter cells by different pathways, multi-drug resistance (MDR) can be minimized. Anti-cancer polymer-drug conjugates can be divided into two targeting modalities: passive and active. Tumor tissues have anatomic characteristics that differ from normal tissues. Macromolecules penetrate and accumulate preferentially in tumors relative to normal tissues, leading to extended pharmacological effects. This "enhanced permeability and retention" (EPR) effect is the principal reason for current successes with macromolecular anti-cancer drugs. Both natural and synthetic polymers have been used as drug carriers, and several bioconjugates have been clinically approved or are in human clinical trials. While clinically useful anti-tumor activity has been achieved using passive macromolecular drug delivery systems, further selectivity is possible by active targeting. Attachment of targeting moieties to the polymer backbone can further exploit differences between cancer and normal cells through selective receptor-mediated endocytosis. This strategy would augment the EPR effect, thereby further improving the therapeutic index of the macromolecular drug. This review discusses the development and therapeutic potential of prototype macromolecular drugs for use in cancer chemotherapy. Specific examples are selected to illustrate the basic design principles for soluble polymeric drug delivery systems.