Biodegradable Micellar HPMA-Based Polymer–Drug Conjugates with Betulinic Acid for Passive Tumor Targeting

Abstract

Here, we present the synthesis, physicochemical, and preliminary biological characterization of micellar polymer-betulinic acid (BA) conjugates based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells. Various HPMA copolymer conjugates differing in the structure of the spacer between the drug and the carrier were synthesized, all designed for pH-triggered drug release in tumor tissue or tumor cells. The high molecular weight of the micellar conjugates should improve the uptake of the drug in solid tumors due to the Enhanced permeability and retention (EPR) effect. Nevertheless, only the conjugate containing BA with methylated carboxyl groups enabled pH-dependent controlled release in vitro. Moreover, drug release led to the disassembly of the micellar structure, which facilitated elimination of the water-soluble HPMA copolymer carrier from the body by renal filtration. The methylated BA derivative and its polymer conjugate exhibited high cytostatic activity against DLD-1, HT-29, and HeLa carcinoma cell lines and enhanced tumor accumulation in HT-29 xenograft in mice.

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

“…These carrier systems are usually developed to stabilize therapeutic compounds, overcoming obstacles to cellular and tissue uptake, improving biodistribution, bioavailability, and therapeutic efficacy, and decreasing the side effects of compounds that target specific sites in vivo. Only a few articles have been published describing the preparation of BA‒polymer conjugates since 2013 [83,84,85,86,87]. Although the synthesis of polymer‒BA conjugates involves mainly amination and esterification reactions, it makes more sense to create a specific section to approach this theme.…”

“…Lomkova et al reported the synthesis, physicochemical, and preliminary biological characterization of micellar polymer‒BA conjugates based on N -(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers, enabling the controlled release of cytotoxic BA derivatives in solid tumors or tumor cells [83]. The synthesis of these polymer‒BA conjugates started with the preparation of BA levulinate (BA-LEV) and BA 3-acetyl acrylate (BA-AA) through esterification reactions of 3-OH group of BA with levulinic acid and 3-acetyl acrylic acid, respectively, using the N , N’ -dicyclohexylcarbodiimide (DCC) coupling method.…”

Therapeutic applications of betulinic acid nanoformulations

“…In a recent study, Lomkova et al . synthesized BA–HPMA copolymer conjugates using different spacers between the BA and the HPMA for pH‐triggered drug release toward tumor cells . The synthesized conjugates were able to form micelles in aqueous solutions with hydrodynamic radii of 12–14 nm owing to the hydrophobic nature of BA.…”

HPMA Copolymer–Drug Conjugates with Controlled Tumor‐Specific Drug Release

“…Later, pH‐sensitive hydrazone spacers were introduced between a hydrophilic polymer carrier and a hydrophobic cholesterol structure to facilitate carrier elimination from the body after disintegration of the HMW micellar structure into short, water‐soluble polymer fragments in tumor tissue . Recently, a highly hydrophobic triterpenoid drug, betulinic acid, was bound to an HPMA polymer carrier by a pH‐sensitive hydrazone spacer based on 4‐oxo‐pentanoic acid . It can be expected that the controlled drug release in the mildly acidic conditions of tumor tissue or cells will be followed by disassembly of polymer micelles, which should facilitate renal removal of the polymer carrier from the body.…”