Assessment of Intracellular Delivery Potential of Novel Sustainable Poly(δ-decalactone)-Based Micelles.

Kuldeep Kumar Bansal,Ezgi Özliseli,Gaurav Kumar Saraogi,Jessica M Rosenholm

doi:10.3390/pharmaceutics12080726

Abstract

Biodegradable polymers from renewable resources have attracted much attention in recent years within the biomedical field. Lately, poly(δ-decalactone) based copolymer micelles have emerged as a potential drug delivery carrier material as a sustainable alternative to fossil-based polymers. However, their intracellular drug delivery potential is not yet investigated and therefore, in this work, we report on the synthesis and cellular uptake efficiency of poly(δ-decalactone) based micelles with or without a targeting ligand. Folic acid was chosen as a model targeting ligand and Rhodamine B as a fluorescent tracer to demonstrate the straightforward functionalisation aspect of copolymers. The synthesis of block copolymers was accomplished by a combination of facile ring-opening polymerisation and click chemistry to retain the structure uniformity. The presence of folic acid on the surface of micelles with diameter ~150 nm upsurge the uptake efficiency by 1.6 fold on folate receptor overexpressing MDA-MB-231 cells indicating the attainment of targeting using ligand functionality. The drug delivery capability of these carriers was ascertained by using docetaxel as a model drug, whereby the in vitro cytotoxicity of the drug was significantly increased after incorporation in micelles 48 h post incubation. We have also investigated the possible endocytosis route of non-targeted micelles and found that caveolae-mediated endocytosis was the preferred route of uptake. This work strengthens the prospect of using novel bio-based poly(δ-decalactone) micelles as efficient multifunctional drug delivery nanocarriers towards medical applications.

Highlights

The majority of pharmacologically active compounds are known to act on targets located within the cell for the treatment of diseases
Poly(ethylene glycol) methyl ether, δ-decalactone (≥98%), 1,5,7-triazabicyclo [4.4.0]dec-5-ene (TBD) (98%), propargyl alcohol (99%), anhydrous pyridine (99.8%), p-toluenesulfonyl chloride (≥99%), sodium azide (≥99.5%), folic acid (≥97%), rhodamine B isothiocyanate(mixed isomer), N,N -dicyclohexylcarbodiimide (99%), N-hydroxysuccinimide (98%), trimethylamine (≥99%), copper (I) bromide (99.9%), and all the solvents were purchased from Sigma Aldrich
Two mixed micelle formulations using the copolymers were fabricated using a nanoprecipitation method, in which one was actively targeted (PDL-Folic acid (FA) micelles), and another was a nontargeted (PDL micelles) formulation. These micelle formulations were tested for cellular uptake efficiency on the MDA-MB-231 cell line

Summary

Introduction

The majority of pharmacologically active compounds are known to act on targets located within the cell for the treatment of diseases. Ligand-mediated targeting, known as active targeting is the most common approach used to deliver drugs intracellularly via nanocarriers [2]. Superior antitumor activities of drug-loaded nanocarriers with active targeting capabilities have been reported due to their enhanced cellular internalisation via receptor-mediated endocytosis. The most common ligands used for targeted drug delivery are sugars, antibodies, nucleic acids, proteins, peptides, and small molecules such as vitamins [3]. Folic acid (FA) as a targeting ligand is the most studied molecule utilised for active targeting in targeted therapy to deliver drug-loaded nanocarriers at the site of action. Several FA-conjugated drug delivery carriers such as liposomes, nanoparticles, micelles, dendrimers, and carbon nanotubes have been investigated for targeted cancer therapy [4]. Based on the excellent in vitro and in vivo results, a few folic acid-based drug delivery systems have been entered in clinical trials [5]

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Results

Conclusion