Prodrugs Forming High Drug Loading Multifunctional Nanocapsules for Intracellular Cancer Drug Delivery

Abstract

Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which showed high in vitro and in vivo antitumor activity. Meanwhile, the resulting nanocapsules can be loaded with a water-soluble drug-doxorubicin salt (DOX.HCl)-with a high loading efficiency. The DOX.HCl-loaded nanocapsules simultaneously delivered two anticancer drugs, leading to a synergetic cytotoxicity to cancer cells. The concept directly using drugs as part of a carrier is applicable to fabricating other highly efficient nanocarriers with a substantially reduced use of inert carrier materials and increased drug loading content without premature burst release.

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

“…As reported previously, combined use of a small molecule drugs and genes with vectors, including liposomes, polymeric micelles, and inorganic nanoparticles, is a promising approach for disease therapy. However, the drug‐loading of these vectors has been low, not greater than 10%,30 thereby discounting therapeutic outcomes. Here, the drug‐loading in CNPs reached up to 500%, and thus this combined strategy has the potential to overcome this limitation of commonly utilized vectors.…”

Co‐Delivery of Drugs and Genes Using Polymeric Nanoparticles for Synergistic Cancer Therapeutic Effects

“…To surmount these limitations, Shen, et al used hydrophobic drugs as a hydrophobic part of the block copolymer or nanoparticles that could minimize the use of other inert materials and increase the drug loading content. [42] For example, SN38 was conjugated to oligo-PEG via a thioether and phenol ester bond formation. [43] In aqueous solutions, the drug conjugates formed polymersomes sensitive to glutathione and reactive oxygen species due to the presence of phenol ester and thioether groups.…”

Nanosized Camptothecin Conjugates for Single and Combined Drug Delivery

“…Shen etc took the advantage of the strong hydrophobicity of camptothecin and conjugated it with short oligo ethylene glycol (OEG) (42). Both single and dual CPT conjugates (OEG-CPT, OEG-DiCPT) self-assem- bled into liposome-like nanoparticles with drug loading as high as 58 wt% (Figure 2c).…”