Multipurpose polymer nanoscaffolds for cellular imaging and delivery of anticancer drug are urgently required for the cancer therapy. The present investigation reports a new polymer drug delivery concept based on biodegradable polycaprolactone (PCL) and highly luminescent π-conjugated fluorophore as dual functional nanocarrier for cellular imaging and delivery vehicles for anticancer drug to cancer cells. To accomplish this goal, a new substituted caprolactone monomer was designed, and it was subjected to ring opening polymerization using a blue luminescent bishydroxyloligo-phenylenevinylene (OPV) fluorophore as an initiator. A series of A-B-A triblock copolymer building blocks with a fixed OPV π-core and variable chain biodegradable PCL arm length were tailor-made. These triblocks self-assembled in organic solvents to produce well-defined helical nanofibers, whereas in water they produced spherical nanoparticles (size ∼150 nm) with blue luminescence. The hydrophobic pocket of the polymer nanoparticle was found to be an efficient host for loading water insoluble anticancer drug such as doxorubicin (DOX). The photophysical studies revealed that there was no cross-talking between the OPV and DOX chromophores, and their optical purity was retained in the nanoparticle assembly for cellular imaging. In vitro studies revealed that the biodegradable PCL arm was susceptible to enzymatic cleavage at the intracellular lysosomal esterase under physiological conditions to release the loaded drugs. The nascent nanoparticles were found to be nontoxic to cancer cells, whereas the DOX-loaded nanoparticles accomplished more than 80% killing in HeLa cells. Confocal microscopic analysis confirmed the cell penetrating ability of the blue luminescent polymer nanoparticles and their accumulation preferably in the cytoplasm. The DOX loaded red luminescent polymer nanoparticles were also taken up by the cells, and the drug was found to be accumulated at the perinuclear environment. The new nanocarrier approach reported in the present manuscript accomplishes both cellular imaging and delivering drugs to intracellular compartments in a single polymer system. The present investigation is one of the first examples to demonstrate the dual functional biodegradable luminescence nanocarrier concept in the literature, and the studies established this proof-of-concept in cellular imaging and drug delivery in cancer cells.

The present investigation reports enzyme-biodegradable perylenebisimide (PBI)-tagged polycaprolactone (PCL) block copolymers, and their aqueous nanoassemblies were employed as probes for intracellular bio-imaging in cancer cells. Bishydroxyl functionalized PBI initiator was tailor-made, and it was employed as initiator for the ring opening polymerization (ROP) methodology to make PBI-tagged tert-butyl ester-substituted polycaprolactone (PBI-BPCL x ) block copolymers. The deprotection of these copolymers yielded carboxylic acid-substituted PBI-CPCL x amphiphilic block copolymers. The carboxylic blocks were self-assembled to produce stable red-fluorescent nanoparticles of <150 nm in size in aqueous medium with fluorescent quantum yield of ϕ = 0.25–0.30 suitable for bio-imaging application. In vitro studies confirmed that the aliphatic polyester backbone in the PBI-CPCL x polymer nanoparticles was readily biodegradable by lysosomal enzymes under physiological conditions. Dynamic light scattering, gel permeation chromatography, photophysical studies, and MALDI-TOF-MS analysis provided evidence of the enzymatic biodegradation. Cytotoxicity studies revealed that the PBI-CPCL x nanoparticles were highly biocompatible toward both cervical cancer and breast cancer cell lines up to a concentration of 100 μg/mL. Confocal microscopy analysis confirmed the uptake and accumulation of red-fluorescent PBI-CPCL x polymer nanoparticles in the perinuclear environment of the cells. The present approach puts forward a PBI-PCL block copolymer design as enzyme-responsive red-fluorescent nanoprobes for bio-imaging in cancer and normal cells.

Fluorescent drug delivery systems have received increasing attention in cancer therapy because they combine drug delivery and bioimaging into a single platform. For example, polymers with aggregation-induced emission (AIE) fluorophores, such as tetraphenylethylene (TPE), have emerged as an elegant choice for drug delivery/bioimaging applications. In this work, we report one-pot sequential organocatalytic ring-opening polymerization of ε-caprolactone (CL) and ethylene oxide (EO) using TPE-(OH) 2 as a difunctional initiator, in the presence of a t-BuP 2 /TEB Lewis pair (catalyst), in THF at room temperature. Two well-defined triblock copolymers with inverse block sequences, TPE-(PCL-b-PEO) 2 and TPE-(PEO-b-PCL) 2 , were synthesized by altering the sequential addition of CL and EO. The physicochemical properties, including hydrodynamic diameter, morphology, and AIE properties of the synthesized amphiphilic triblock copolymers were investigated in aqueous media. The block copolymer micelles were loaded with anticancer drugs doxorubicin and curcumin to serve as drug delivery vehicles. In vitro studies revealed the accelerated drug release at lower pH (5.5), which mimics the tumor microenvironment, different from the physiological pH (7.4). In vitro cytotoxicity studies demonstrated that the neat block copolymer micelles are biocompatible, while drug-loaded micelles exhibited a significant cytotoxic effect in cancer cells. Cellular uptake, examined by confocal laser scanning microscopy, showed that the block copolymer micelles were rapidly internalized by the cells with simultaneous emission of TPE fluorophore. These results suggest that these triblock copolymers can be utilized for intracellular bioimaging.

The present investigation reports a new fluorophore-tagged biodegradable polycaprolactone (PCL) block copolymer FRET-probe for intracellular imaging in cancer therapy. A hydroxyl functionalized π-conjugated oligo-phenylenevinylene (OPV) chromophore was tailor-made, and it was incorporated in a t-butyl ester substituted polycaprolactone block copolymer via ring opening polymerization. This blue-luminescent OPV-PCL triblock self-assembled as <200 nm spherical nanoparticles (FRET donor), and it encapsulated water insoluble Nile red (NR, FRET acceptor) to yield an OPV-NR FRET probe. Selective photo excitation of the OPV chromophore in block nanoassemblies enabled the excitation energy transfer from the OPV to NR and facilitated the efficient FRET process in aqueous medium. Time-correlated fluorescent decay dynamics and detailed photophysical studies were carried out to estimate the Förster distance, donor–acceptor distance, and the excitation energy transfer efficiency. These parameters confirmed the occurrence of the FRET process within the confined nanoparticle environment. The PCL chains in the FRET probe were susceptible to enzymatic biodegradation in intracellular environments, and the degradation process controlled the FRET on/off mechanism. Cytotoxicity studies revealed that the FRET probe was biocompatible and nontoxic to cells, and the FRET-probe was found to be readily taken up by the cancer cells, and it was internalized in the cytoplasm and peri-nuclear environment. Selective photoexcitation of the OPV chromophore in a confocal microscope exhibited dual emission from the FRET probe. The cancer cells exhibited blue luminescence (self-emission) with respect to the OPV chromophore (in the blue channel) and bright red-luminescence from the NR dye followed by the FRET process at the cellular level (in the red channel). The dual luminescence characteristics, biodegradation and biocompatibility, make the newly designed PCL-OPV-NR FRET probe an excellent biomedical nanodevice for bioimaging applications, and the proof-of-concept was established in cervical (HeLa) and breast cancer (MCF 7) cell lines.

Monitoring intracellular administration of nonluminescent anticancer drugs like cisplatin is a very challenging task in cancer research. Perylenebisimide (PBI) chromophore tagged fluorescent ABC-triblock polycaprolactone (PCL) nanoscaffold was engineered having carboxylic acid blocks for the chemical conjugation of cisplatin at the core and hydrophilic PEG blocks at the periphery. The amphiphilic ABC triblock Pt-prodrug was self-assembled into < 200 nm nanoparticles and exhibited excellent shielding against drug detoxification by the glutathione (GSH) species in the cytosol.In vitro drug release studies confirmed that the Pt-prodrug was stable at extracellular conditions and the PCL block exclusively underwent lysosomal-enzymatic biodegradation at the intracellular level to release the cisplatin drug in the active-form for accomplishing more than 90% cell growth inhibition. Confocal microscopic imaging of the redfluorescence signals from the perylene chromophores established the simultaneous monitoring and delivery aspects of the Pt-prodrug, and the proof-of-concept was successfully demonstrated in breast and cervical cancer cell lines.