Polymer Topology Driven Enzymatic Biodegradation in Polycaprolactone Block and Random Copolymer Architectures for Drug Delivery to Cancer Cells

Abstract

The present investigation reports polymer topology design principle for programming the enzymatic biodegradation and delivery of anticancer drugs at the intracellular compartments of breast and cervical cancers. To accomplish this goal, new classes of biodegradable amphiphilic block and random copolymers based on hydrophilic carboxylic-functionalized polycaprolactone (CPCL) and hydrophobic polycaprolactone (PCL) units were designed via ring-opening polymerization methodology. The interchain interactions and their packing were directly controlled by the topology of the polymers, and the block copolymers were found to be as semicrystalline materials. These amphiphilic block and random polymers were readily dispersible in water, and they self-assembled into <200 nm nanoparticles. These nanoparticles exhibited excellent capability for loading anticancer drug doxorubicin (DOX) in the hydrophobic pocket. In vitro drug release kinetics revealed that the polymer nanoscaffolds were stable under physiological conditions, and they exclusively ruptured in the presence of lysosomal esterase enzyme at the intracellular compartments to deliver DOX. The “burst” and “controlled” release of drugs from the polymer nanocarriers was directly controlled by length and chemical composition of block and random copolymers. In vitro cytotoxicity studies in breast cancer (MCF 7) and cervical cancer (HeLa) cells revealed that the nascent polymer nanoparticle was highly biocompatible and nontoxic to cells whereas their DOX-loaded nanoparticles accomplished >95% cell killing. Confocal microscopy reinstated the cellular uptake of the DOX-loaded polymer scaffold wherein the nanoparticle was highly concentrated at the nucleus and revealed that the drugs were predominantly delivered at the nucleus of the cells for apoptosis. Flow cytometry investigation confirmed the enhanced DOX delivering capability of block and random copolymer nanoparticles compared to free DOX. The newly designed fully biodegradable PCL-based block and random nanocarriers are excellent scaffolds for enzyme-mediated intracellular delivery of DOX, and the proof of concept was established in breast and cervical cancers.

Preparation of poly(butylene succinate)‐poly[2‐(dimethylamino)ethyl methacrylate] copolymers and their applications as carriers for drug delivery

“…PDBD 23 was selected to investigate the loading and release characters of drugs in the micelles using DOX as a model drug. DOX was selected as it is a powerful anticancer drug while having poor solubility in water . First, DOX‐loaded PDBD 23 micelles were fabricated by a solvent evaporation method.…”

“…DOX was selected as it is a powerful anticancer drug while having poor solubility in water. 40,41 First, DOX-loaded PDBD 23 micelles were fabricated by a solvent evaporation method. The results (Fig.…”

Evaluation of electron beam‐induced crosslinking of poly(ε‐caprolactone)—Effect of elevated temperatures

“…In recent years, biodegradable polymers have attracted great interests in biomedicine, as they can act as temporary scaffolds which promote the regeneration of tissues or the cell growth . Among the biodegradable polymers, poly(ε‐caprolactone) (PCL) has been extensively studied in different fields, such as tissue engineering, medical devices, and packaging due to its favorable biocompatibility and biodegradability profiles . Recently, the environmentally friendly packaging material designed especially for drugs and food is one of the most significant commercial applications of PCL.…”

“…1,2 Among the biodegradable polymers, poly(ε-caprolactone) (PCL) has been extensively studied in different fields, such as tissue engineering, medical devices, and packaging due to its favorable biocompatibility and biodegradability profiles. [3][4][5] Recently, the environmentally friendly packaging material designed especially for drugs and food is one of the most significant commercial applications of PCL. However, the commercially available PCL with a linear chain structure has insufficient heat resistance, low melt strength, and deficient thermomechanical strength, greatly restricting its processability such as thermoforming, foaming as well as blow molding.…”

Covalent polyester-biomolecule conjugates: advances in their synthesis and applications in biomedicine and nanotechnology

“…For instance, the use of polycaprolactone (PCL), which is approved by the US Food and Drug Administration, as scaffolds for tissue engineering is established, and diverse cells have been cultured on PCL with various copolymer compositions and/or hydrophilicity . PCL copolymers find also many applications in drug delivery . Polyhydroxyalkanoates (PHAs) are also very important polyesters with applications in biology and medicine, which – due to their crystalline nature – often have to be hydrophilized with poly(ethylene glycol) (PEG) to afford PHA–PEG copolymers .…”