Intracellular Delivery of Drugs to Macrophages

Abstract

Toxic side effects which often complicate successful therapy in a number of diseases possibly arise due to the fact that at therapeutically effective concentrations the non-target cells in the body are also exposed to the cytotoxic effects of the drugs. Minimization of such adverse reactions might be feasible through drug delivery modalities that would reduce the uptake of the drugs by non-target cells and selectively deliver the drug only to the target cells (and/or intracellular sites) at relatively low extracellular concentrations. The current generic approach to site-specific drug delivery consists of attaching the therapeutic agent to a carrier recognized only by the cells where the pharmacological action is desired. Two types of recognition elements on the surface of target cells are being exploited for this purpose, viz., (i) antigens capable of generating specific, non-cross reactive antibodies, and (ii) receptors on the cell surface capable of efficient transport of the ligands. In general, incomplete specificity for the target cells and poor internalization of antibody-drug conjugates still limit the usefulness of antibodies for site-specific drug delivery applications necessitating exploration of alternatives. The alternate possibility is to exploit the exquisite cell type specificity and high efficiency of endocytosis of macromolecules mediated by specific receptors present on the surface of target cells for delivering drugs. A large number of infectious, metabolic, and neoplastic diseases are associated with macrophages leading to morbidities and mortalities to millions of people worldwide, thus an appropriate design of a drug delivery system to macrophages will be of tremendous help.

Preparation, Characterization and Evaluation of Targeting Potential of Amphotericin B-Loaded Engineered PLGA Nanoparticles

“…The percentage uptake in J774A.1 macrophages followed this order: engineered PNPs with spacer > engineered PNPs without spacer > plain PNPs. Such internalization by engineered PNPs could be attributed to RME that may lead to enhanced phagocytosis (12). Additionally, higher uptake of engineered PNPs over PNPs also provides the evidence that RME predominated over normal phagocytosis involved in uptake and internalization of particulate carrier.…”

“…Mukhopadhya and Basu (12) reviewed the intracellular delivery of drugs to macrophages by RME using mannose and scavenger receptors for various macrophage-specific diseases like visceral leishmaniasis (VL). Previously, cytotoxic drugs, such as methotrexate and doxorubicin, were conjugated to mannose-specific neoglycoproteins for active targeting to macrophages and were found to be highly effective against VL (11,13).…”

Amphotericin B-loaded mannose modified poly(d,l-lactide-co-glycolide) polymeric nanoparticles for the treatment of visceral leishmaniasis: in vitro and in vivo approaches

“…In addition, this mannose associated drug delivery to the macrophages could generally occur by receptor-mediated endocytosis, using the mannose receptor in the case of VL. 20 Many research works have been carried out where polyethylene glycol was used as a spacer between the ligand, mannose and the drug encapsulated polymer for this kind of drug delivery system, but it is expected that the exible long chains of polyethylene glycol could shield the mannose, making them unable to interact with the mannose receptor. 21 Therefore we attached a stearoyl moiety to the mannose to synthesize Ostearoyl mannose, which might circumvent this problem.…”

Reactive oxygen species are the major antibacterials against Salmonella Typhimurium purine auxotrophs in the phagosome of RAW 264.7 cells

“…However, the discovery of several minor differences in purine and pyrimidine biosynthetic pathways between eukaryotic cells and their intracellular parasites has recently encouraged research in this area and led to the development of specific anti‐ Mycobacterial drugs which display minimal cytotoxicity for host cells (Bakkestuen et al ., 2005). Further selectivity in action might be afforded through macrophage‐targeted liposomal drug delivery of antimicrobials, which has been demonstrated for multiple pathogens including S. Typhimurium (Coune, 1988; Mukhopadhyay and Basu, 2003; Owais and Gupta, 2005), suggesting that selective inhibition of enzymes of the purine nucleotide biosynthetic pathway offers a rational therapeutic paradigm. We are currently exploring the selective toxicity of purine analogues and the capacity of inhibitors of purine nucleotide biosynthesis to inhibit intracellular replication of virulent Salmonellae.…”