A Smart Nano‐Prodrug Platform with Reactive Drug Loading, Superb Stability, and Fast Responsive Drug Release for Targeted Cancer Therapy

Abstract

Nano-prodrugs usually involve a multistep synthesis which largely compromises their benefits. Here, a smart nano-prodrug platform with reactive drug loading, superb stability, and triggered drug release is reported for targeted melanoma therapy. cRGD-decorated polymersomal mertansine prodrug (cRGD-PS-DM1) is readily fabricated from cRGD-functionalized poly(ethylene glycol)-b-poly(trimethylene carbonate-co-dithiolane trimethylene carbonate) with simultaneous loading of mertansine (DM1) via thiol-disulfide exchange reaction and disulfide cross-linking of polymersomal membrane. cRGD-PS-DM1 exhibits a size of ≈100 nm, little drug leakage, and fast DM1 release in the presence of 2 × 10 −3 -10 × 10 −3 m glutathione. Tetrazolium-based colorimetric assay (MTT) and confocal microscopy studies confirm effective homing of cRGD-PS-DM1 to α v β 3 overexpressing B16F10 melanoma cells. Notably, the in vivo studies show that cRGD-PS-DM1 has a greatly improved toleration as compared with free DM1 and effectively inhibits tumor growth and extends the survival time of B16F10 melanoma-bearing mice. cRGD-PS-DM1 nanoprodrug with reactive drug loading and multifunction provides an advanced nanomedicine for cancer therapy.

Recent progress in drug delivery

“…The cRGD-decorated polymersomal mertansine prodrug (cRGD-PS-DM1) has been readily fabricated from cRGD-functionalized poly(ethylene glycol)- b -poly(trimethylene carbonate- co -dithiolane trimethylene carbonate) with simultaneous loading of mertansine (DM1) via thiol-disulfide exchange reaction and disulfide cross-linking of polymersomal membrane. The study showed that cRGD-PS-DM1 has high drug loading, superior stability, and fast responsive drug release 156 .…”

“…Prodrug nanomedicine self-assembled by amphiphilic prodrug usually achieves high drug loading and stability153, 155, 156. pH-responsive micellar nanoparticles are prepared by self-assembly of an amphiphilic poly(ethylene glycol)-acetal-paclitaxel (PEG-acetal-PTX) prodrug, and free PTX can be encapsulated in the hydrophobic core of the nanoparticles.…”

Nanoparticulation of Prodrug into Medicines for Cancer Therapy

“…Nanoformulation of prodrugs, a combination of prodrug strategy and nanotechnology tactics, inherits the merits both hence holds a few advantages, such as high drug loading efficiency, improved drug availability and enhanced accumulation in cancer cells in terms of drug delivery. Reactive drug loading, decent stability, and triggered drug release and targeted therapy [ 250 ] are the four essential components of a smart nanoprodrug platform and should improve the pharmacokinetics and decrease toxicity of the chemotherapeutic by transforming an encapsulated prodrug to tumor sites, where it is selectively released and converted to active parent drug.…”

Stimuli-Responsive Aliphatic Polycarbonate Nanocarriers for Tumor-Targeted Drug Delivery

“…The confocal microscopy studies have shown active tumor-targeting by cRGD-decorated nanoparticles to α v β 3 integrin overexpressing melanoma cells. In vivo experiments revealed a significant tumor growth inhibition with cRGD-functionalized nanoparticles loaded with mertansine when compared with non-targeting nanoparticles loaded with drug and free mertansine [116]. Another well-known receptor-mediated tumor-targeting moiety is folic acid.…”