The present investigation reports the structural engineering of biodegradable star block polycaprolactone (PCL) to tailor-make aggregated micelles and unimolecular micelles to study their effect on drug delivery aspects in cancer cell lines. Fully PCL-based star block copolymers were designed by varying the arm numbers from two to eight while keeping the arm length constant throughout. Multifunctional initiators were exploited for stepwise solvent-free melt ring-opening polymerization of ε-caprolactone and γ-substituted caprolactone to construct star block copolymers having a PCL hydrophobic core and a carboxylic PCL hydrophilic shell, respectively. A higher arm number and a higher degree of branching in star polymers facilitated the formation of unimolecular micelles as opposed to the formation of conventional multimicellar aggregates in lower arm analogues. The dense core of the unimolecular micelles enabled them to load high amounts of the anticancer drug doxorubicin (DOX, ∼12–15%) compared to the aggregated micelles (∼3–4%). The star unimolecular micelle completely degraded leading to 90% release of the loaded drug upon treatment with the lysosomal esterase enzyme in vitro. The anticancer efficacies of these DOX-loaded unimolecular micelles were tested in a breast cancer cell line (MCF-7), and their IC50 values were found to be much lower compared to those of aggregated micelles. Time-dependent cellular uptake studies by confocal microscopy revealed that unimolecular micelles were readily taken up by the cells, and enhancement of the drug concentration was observed at the intracellular level up to 36 h. The present work opens new synthetic strategies for building a next-generation biodegradable unimolecular micellar nanoplatform for drug delivery in cancer research.

We report self-reporting fluorescent polysaccharide polymersome nanoassemblies for enzyme-responsive intracellular delivery of two clinical anticancer drugs doxorubicin (DOX) and cisplatin to study the real-time drug-releasing aspects by fluorescent resonance energy transfer (FRET) bioimaging in live cancer cells. Fluorescent polymersomes were tailor-made by tagging an aggregation-induced emission (AIE) optical chromophore, tetraphenylethylene (TPE), and a plant-based vesicular directing hydrophobic unit through enzyme-biodegradable aliphatic ester chemical linkages in the polysaccharide dextran. The blue-luminescent polymersome self-assembled in water and exhibited excellent encapsulation capability for the red-luminescent anticancer drug DOX. FRET between the AIE polymersome host and DOX guest molecules resulted in a completely turn-off probe. At the intracellular level, the lysosomal enzymatic disassembly of the polymersome restored the dual fluorescent signals from DOX and TPE at the nucleus and the lysosomes, respectively. Live-cell confocal microscopy coupled with selective photoexcitation was employed to study the real-time polymersome disassembly by monitoring the turn-on fluorescent signals in human breast cancer cell lines. Alternatively, carboxylic acid-functionalized AIE polymersomes were also tailor-made for cisplatin stitching to directly monitor Pt drug delivery. The polymersome nanoassemblies exhibited excellent structural tolerance for the chemical conjugation of the Pt drugs, and the fluorescence signals were unaltered. An in vitro drug release study confirmed that the cisplatin-stitched fluorescent polymersomes were very stable under physiological conditions and underwent lysosomal enzymatic degradation to inhibit the cancer cell growth. A lysosomal colocalization experiment using confocal microscopy substantiates the enzyme-responsive degradation of these polymersomes to release both the encapsulated and conjugated drugs at the intracellular level. The present design provides a unique opportunity to deliver more than one anticancer drug from a single polymersome platform in cancer research.