Injectable biodegradable polymer depots for minimally invasive delivery of peptides and proteins.

With hundreds of biotechnological drugs, mostly peptides and proteins, undergoing clinical trials, there is an urgent need for improved methods to deliver these magnificent biomacromolecules. Unfortunately, when administered to the body by noninvasive routes, most peptide and protein drugs suffer from significant biological barriers such as poor drug permeability across intestinal mucosa and susceptibility to proteolysis, which in turn, prevents the drug from reaching the systemic circulation and the desired pharmacological target. Therefore, this class of drug molecules is most commonly delivered by injection (e.g., subcutaneously (s.c.) or intravenously (i.v.)) allowing immediate (i.v.) or easy (s.c.) access to the blood circulation. However, even when administered i.v., the body normally eliminates the drug rapidly, requiring the drug be injected repeatedly (e.g., multiple times a day or week). Frequent injections often result in significant pain, poor patient compliance, physiological stress, and peak-and-valley drug levels in the bloodstream. Several promising methods to overcome difficulties with peptide and protein delivery have been pursued, such as a) altering the chemical structure of drug molecule to increase plasma half-life (e.g., PEGylation), b) utilizing mucosal routes with improved drug bioavailability (e.g., pulmonary and intranasal), and c) extending drug release by microencapsulating the drug in biodegradable polymer depots. Injection frequency can be reduced from daily injections to 1–6 months for current marketed controlled-release peptide formulations, which are prepared from the most common biodegradable polymer for long-term controlled release, poly(lactic-co-glycolic acid) (PLGA). PLGA as a polyester degrades by nonenzymatic hydrolysis to yield nontoxic byproducts while slowly and continuously releasing the medication. PLGA depots have successfully been used to treat a variety of diseases, including those afflicting children and young adults, e.g., central precocious puberty (leuprolide acetate) [1], acromegaly (octreotide acetate) [2], disorders of short stature (human growth hormone) [3], and endometriosis (leuprolide) [1]. In addition to systemic delivery of polypeptides, injectable PLGA depots are also used for drug delivery directly to the target (i.e., so-called “site-specific drug delivery”), e.g., allowing novel growth factors to promote growth of new blood vessels (e.g., basic fibroblast growth factor) or bone (e.g., bone morphogenetic proteins). PLGA depots are not limited to drug delivery and are among the most sought after alternative to aluminum-based adjuvants, which are the only adjuvants approved for human use in the US, and are used to deliver childhood vaccines. Finally, novel peptide antigens, which currently cannot be delivered effectively with aluminum compounds may also benefit from this safe and flexible dosage form. Despite tremendous progress in development of injectable peptide depots, several issues have impeded their more widespread development. Important obstacles include: a) stability of the peptide/protein when encapsulated in the polymer, b) a difficulty to microencapsulate simply and inexpensively, c) poor control of drug release over the first day following administration (i.e., the initial burst release), and d) a low immune response to PLGA-encapsulated peptide antigens. We summarize here two examples of our approaches to overcome these limitations, namely: a) stabilization of PLGA-encapsulated bFGF to promote blood reperfusion and rescue ischemic SCID murine hindlimbs [4, 5], and b) the strong and unexpected enhancement of the antibody response to a birth control peptide antigen encapsulated in pH-modified PLGA [6].