N-Succinyl-(β-alanyl-l-leucyl-l-alanyl-l-leucyl)doxorubicin:  An Extracellularly Tumor-Activated Prodrug Devoid of Intravenous Acute Toxicity

Abstract

Intravenous administration of N-(beta-alanyl-L-leucyl-L-alanyl-L-leucyl)doxorubicin (4) induces an acute toxic reaction, killing animals in a few minutes. This results from its positive charge at physiological pH combined with its propensity to form large aggregates in aqueous solutions. Negatively charged N-capped versions of 4 such as the succinyl derivative 5 can be administered by the iv route at more than 10 times the LD(50) of doxorubicin without inducing the acute toxic reaction, and they are active in vivo.

Targeted pharmaceutical nanocarriers for cancer therapy and imaging

“…The therapeutic ap plication of hydrophobic, poorly water-soluble agents is associated with some serious problems, since low watersolubility results in poor absorption and low bioavailability. 28 In addition, drug aggregation upon intravenous administration of poorly soluble drugs might lead to such complications as embolism 29 and local toxicity. 30 On the other hand, the hydrophobicity and low solubility in water appear to be intrinsic properties of many drugs, 31 since it helps a drug molecule to penetrate a cell membrane and reach important intracellular targets.…”

Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs

“…Thus, i.v. administration of aggregates formed by undissolved drug in aqueous media can cause embolization of blood capillaries (Յ5 m) before drug penetrates a tumor (8). Additionally, low solubility of hydrophobic drugs in combination with excretion and metabolic degradation hinders the maintenance of therapeutically significant systemic concentrations.…”

Study of block copolymer micelles as vehicles for hydrophobic drug Lamotrigine

“…Twenty seven Lamotrigine polymeric micelles formulation were prepared according to 3 3 factorial design employing the factors and levels shown in (Table1and2).…”

“…2 In addition, drug aggregation upon intravenous administration of poorly soluble drugs may lead to such complications as embolism 3 and local toxicity. 4 To overcome systemic toxicity a very promising approach is the application of drug-loaded nanosized drug carriers, such as micelles , polymeric nanoparticles, dendrimers and liposomes.…”