Molecularly Precise Dendrimer–Drug Conjugates with Tunable Drug Release for Cancer Therapy

Abstract

The structural preciseness of dendrimers makes them perfect drug delivery carriers, particularly in the form of dendrimer-drug conjugates. Current dendrimer-drug conjugates are synthesized by anchoring drug and functional moieties onto the dendrimer peripheral surface. However, functional groups exhibiting the same reactivity make it impossible to precisely control the number and the position of the functional groups and drug molecules anchored to the dendrimer surface. This structural heterogeneity causes variable pharmacokinetics, preventing such conjugates to be translational. Furthermore, the highly hydrophobic drug molecules anchored on the dendrimer periphery can interact with blood components and alter the pharmacokinetic behavior. To address these problems, we herein report molecularly precise dendrimer-drug conjugates with drug moieties buried inside the dendrimers. Surprisingly, the drug release rates of these conjugates were tailorable by the dendrimer generation, surface chemistry, and acidity.

A multifunctional PEG–PLL drug conjugate forming redox-responsive nanoparticles for intracellular drug delivery

“…5,12,19 Drugs are generally loaded in polymer micelles or nanoparticles via physical trapping by hydrophobichydrophobic interaction, but micelles or core-shell nanoparticles are at equilibrium with their unimers. The anticancer drugs including doxorubicin (DOX) or cisplatin were anchored to the polymers by a hydrazone linkage which allows the polymeric micelles to release drugs selectively at acidic pH (4)(5)(6). 20 One approach to overcome these problems is to conjugate drugs to the nanoparticles core via cleavable linkers triggered by intracellular stimuli such as pH, 21-23 glutathione 24,25 or enzymes, [26][27][28] enabling cytosolic drug release.…”

Cell-Penetrating Hyperbranched Polyprodrug Amphiphiles for Synergistic Reductive Milieu-Triggered Drug Release and Enhanced Magnetic Resonance Signals

“…The extremely hydrophobic CPT prodrugs located within hyperbranched cores can avoid interactions between CPT and blood components to optimize pharmacokinetics and preclude CPT from undesired conversion into the inactive carboxylate form. 12 The polyprodrug strategy possesses combined advantages such as facile preparation, high drug loading, caged drug activity, and triggered release of drugs in the active form. 11,13 The hyperbranched polyprodrug cores serve as the embedding matrix for T1 type MR contrast agents to weaken MR background signals.…”

Preclinical studies of dendrimer prodrugs

“…The intravenous injection of the aminoterminal CPT--dendrimer conjugate resulted in significant antitumor effects, but the toxicity of this material was relatively high. The use of 2,3-dimethylmaleic amide-bearing CPT--dendrimer conjugate led to a reduction in the toxicity, while retaining an antitumor activity similar to that of the amino-terminal form of the conjugate [45].…”