Self-Assembling, Amphiphilic Polymer–Gemcitabine Conjugate Shows Enhanced Antitumor Efficacy Against Human Pancreatic Adenocarcinoma

Abstract

The therapeutic efficacy of gemcitabine is severely compromised due to its rapid plasma metabolism. Moreover, its hydrophilicity poses a challenge for its efficient entrapment in nanosized delivery systems and to provide a sustained release profile. In this study, gemcitabine was covalently conjugated to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (PEG-PCC) which could self-assemble into micelles of 23.6 nm. These micelles afforded protection to gemcitabine from plasma metabolism as evident by negligible amount of gemcitabine and its metabolite dFdU detected in the plasma after 24 h. A controlled release of gemcitabine from the micelles was observed with 53.89% drug release in 10 days in the presence of protease enzyme Cathepsin B. Gemcitabine conjugated micelles were cytotoxic, showed internalization, and induced cell apoptosis in MIA PaCa-2 and L3.6pl pancreatic cancer cell lines. These micelles efficiently inhibited tumor growth when injected intravenously into MIA PaCa-2 cell derived xenograft tumor bearing NSG mice at a dose of 40 mg/kg in terms of reduced tumor volume and tumor weight (0.38 g vs 0.58 g). TUNEL assay revealed that gemcitabine conjugated micelles induced a much higher extent of apoptosis in the tumor tissues compared to free gemcitabine. In conclusion, gemcitabine conjugated micelles were able to enhance the drug payload, protect it from rapid plasma metabolism, and provide a sustained release and showed enhanced antitumor activity, and thus have the potential to provide a better therapeutic alternative for treating pancreatic cancer.

Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis

“…Therefore, in this study, we conjugated DTX and CYP to a biodegradable amphiphilic diblock copolymer mPEG-b-PCC with pendant carboxyl acid groups. We previously conjugated a water soluble drug gemcitabine as well as dodecanol to mPEG-b-PCC, which self-assembled into micelles and showed enhaced drug delivery to pancreatic tumor, which resulted in significant reduction in tumor growth [20–22]. In this study, DTX was conjugated to mPEG-b-PCC through an ester bond at its 2′-OH position.…”

Self-assembling prodrugs

“…Mahato and co-workers, for example, conjugated Gem and dodecanol (C 12 H 25 OH) to a PEG- b -PCC (poly(2-methyl-2-carboxyl-propylene carbonate) polymer through amide and ester linkages, respectively (Figure 5a). 67 This conjugate formed spherical micelles averaging 24 nm in diameter and with a drug loading of almost 13%. In vivo studies indicated a significant increase in effectiveness over free Gem.…”

Hierarchically designed hybrid nanoparticles for combinational photochemotherapy against a pancreatic cancer cell line

“…micelles), which is critical for deep tumor permeation of the pancreas, 8 controllable release of GEM, and active tumor targeting via the installation of tumor targeting ligands. [9][10][11][12][13][14][15] Recently, photothermal therapy (PTT) has shown great potential in cancer treatment. 16 PTT comprises the thermal ablation of cancer cells using a red/near-infrared (NIR) laser photoabsorber such as noble metal nanostructures, 17,18 transition metal sulphides/oxides nanomaterials 19,20 and other nanoagents.…”