No abstract

Drug design is built on the concept that key molecular targets of disease are isolated in the diseased tissue. Systemic drug administration would be sufficient for targeting in such a case. It is, however, common for enzymes or receptors that are integral to disease to be structurally similar or identical to those that play important biological roles in normal tissues of the body. Additionally, systemic administration may not lead to local drug concentrations high enough to yield disease modification because of rapid systemic metabolism or lack of sufficient partitioning into the diseased tissue compartment. This review focuses on drug delivery methods that physically target drugs to individual compartments of the body. Compartments such as the bladder, peritoneum, brain, eye and skin are often sites of disease and can sometimes be viewed as “privileged,” since they intrinsically hinder partitioning of systemically administered agents. These compartments have become the focus of a wide array of procedures and devices for direct administration of drugs. We discuss the rationale behind single compartment drug delivery for each of these compartments, and give an overview of examples at different development stages, from the lab bench to phase III clinical trials to clinical practice. We approach single compartment drug delivery from both a translational and a technological perspective.

No abstract

No abstract

No abstract

Intraperitoneal (IP) chemotherapy for ovarian cancer treatment prolongs overall survival by 16 months compared to intravenous chemotherapy but is not widely practiced due to catheter-related complications and complexity of administration. An implantable, nonresorbable IP microdevice was used to release chemotherapeutic agent at a constant rate of approximately 1.3 µg/hour in vitro and 1.0 µg/hour in vivo. Studies conducted in two orthotopic murine models bearing human xenografts (SKOV3 and UCI101) demonstrate that continuous dosing reduces tumor burden to the same extent as weekly IP bolus drug injections. Treatment-induced toxicity was quantified via body weight loss and complete blood count. The microdevice resulted in significantly less toxicity than IP bolus injections, despite administration of higher cumulative doses (total area under the concentration-time curve of 3,049 ng-day/mL with the microdevice vs. 2,118 ng-day/mL with IP bolus injections). This preclinical study supports the concept that reduced toxicity with similar efficacy outcomes can be achieved by continuous dosing in ovarian cancer patients currently treated with IP therapy.

No abstract

46 Gynecologic and gastrointestinal malignancies are two of the most prevalent cancer types in low and middle- income countries (LMICs), affecting more than 2 million individuals and killing more than 1 million patients annually. These malignancies at an advanced stage metastasize locally but extensively; this spread is a primary cause of morbidity and mortality, affecting 60-80% of patients in LMICs. Localized chemotherapy can benefit survival of patients with such metastases. Localized chemotherapy is, however, essentially unattainable in resource-limited settings, even though many chemotherapy agents are on the WHO list of essential medicines and are currently off patent. This is because of the high cost of, and frequent hospitalizations required under, the current regimen, as well as the morbidity of bolus dosing. Continuous, low-dose chemotherapy via a locally implanted device can address these adoption barriers. Previous attempts to create implants for localized chemotherapy delivery have been hindered by poorly controlled drug release and inhibiting form factors. This work explores the development of a nonresorbable and laparoscopically deployable implant to administer continuous low-dose chemotherapy. The feasibility of chemotherapy using the proposed implant in LMICs is assessed using physician interviews and literature reviews. Tissue-like silicone elastomers are used to create a matrix-type drug delivery implant that minimizes soft tissue irritation and risk of rupture while allowing laparoscopic manipulation. The synthesis and drug release profile of the silicone-based matrix are characterized for small hydrophilic active agents. Configurations allowing implant deployment through laparoscopic instruments are explored. Proof-of-concept controlled release of a hydrophilic small molecule from a lipophilic, tissue-like silicone elastomer that can be scaled to human form factors is thus established. Localized, low-dose chemotherapy delivered via a fully implantable device holds promise to dramatically reduce the cost and resources necessary for treating advanced-stage gynecologic and gastrointestinal malignancies in LMICs, improving cancer patient outcomes in resource-limited settings. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST: Aikaterini Mantzavinou No relationship to disclose Michael J. Cima Leadership: T2 Biosystems, MicroChips Biotechnologies, Taris BioMedical Stock or Other Ownership: T2 Biosystems, MicroChips Biotechnologies, Taris BioMedical Research Funding: Pfizer Patents, Royalties, Other Intellectual Property: Too many to describe (over 50 patents) Expert Testimony: Apotex Laura Melanie Tanenbaum Patents, Royalties, Other Intellectual Property: System and Method for Sterile Sheathing of a Medical Probe