Kulkarni Bhagyashree, Qutub Somayah, Khashab Niveen M, Hadjichristidis Nikos
Polymer Synthesis Laboratory, Chemistry Program, KAUST Catalysis Center, Physical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal 23955, Saudi Arabia.
Smart Hybrid Materials (SHMs) Laboratory, Chemistry Program, Advanced Membranes and Porous Materials Center, King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia.
ACS Omega. 2023 Jun 14;8(25):22698-22707. doi: 10.1021/acsomega.3c01514. eCollection 2023 Jun 27.
The clinical development of the anticancer drug chlorambucil (CHL) is limited by its low solubility in water, poor bioavailability, and off-target toxicity. Besides, another constraint for monitoring intracellular drug delivery is the non-fluorescent nature of CHL. Nanocarriers based on block copolymers of poly(ethylene glycol)/poly(ethylene oxide) (PEG/PEO) and poly(ε-caprolactone) (PCL) are an elegant choice for drug delivery applications due to their high biocompatibility and inherent biodegradability properties. Here, we have designed and prepared block copolymer micelles (BCM) containing CHL (BCM-CHL) from a block copolymer having fluorescent probe rhodamine B (RhB) end-groups to achieve efficient drug delivery and intracellular imaging. For this purpose, the previously reported tetraphenylethylene (TPE)-containing poly(ethylene oxide)--poly(ε-caprolactone) [TPE-(PEO--PCL)] triblock copolymer was conjugated with RhB by a feasible and effective post-polymerization modification method. In addition, the block copolymer was obtained by a facile and efficient synthetic strategy of one-pot block copolymerization. The amphiphilicity of the resulting block copolymer TPE-(PEO--PCL-RhB) led to the spontaneous formation of micelles (BCM) in aqueous media and successful encapsulation of the hydrophobic anticancer drug CHL (CHL-BCM). Dynamic light scattering and transmission electron microscopy analyses of BCM and CHL-BCM revealed a favorable size (10-100 nm) for passive targeting of tumor tissues the enhanced permeability and retention effect. The fluorescence emission spectrum (λ 315 nm) of BCM demonstrated Förster resonance energy transfer between TPE aggregates (donor) and RhB (acceptor). On the other hand, CHL-BCM revealed TPE monomer emission, which may be attributed to the π-π stacking interaction between TPE and CHL molecules. The drug release profile showed that CHL-BCM exhibits drug release in a sustained manner over 48 h. A cytotoxicity study proved the biocompatibility of BCM, while CHL-BCM revealed significant toxicity to cervical (HeLa) cancer cells. The inherent fluorescence of RhB in the block copolymer offered an opportunity to directly monitor the cellular uptake of the micelles by confocal laser scanning microscopy imaging. These results demonstrate the potential of these block copolymers as drug nanocarriers and as bioimaging probes for theranostic applications.
抗癌药物苯丁酸氮芥（CHL）的临床开发受到其在水中溶解度低、生物利用度差和脱靶毒性的限制。此外，监测细胞内药物递送的另一个限制是CHL的非荧光性质。基于聚（乙二醇）/聚（环氧乙烷）（PEG/PEO）和聚（ε-己内酯）（PCL）的嵌段共聚物的纳米载体因其高生物相容性和固有的生物降解性，是药物递送应用的理想选择。在此，我们设计并制备了含有CHL的嵌段共聚物胶束（BCM-CHL），该胶束由具有荧光探针罗丹明B（RhB）端基的嵌段共聚物制成，以实现高效的药物递送和细胞内成像。为此，通过一种可行且有效的后聚合改性方法，将先前报道的含四苯乙烯（TPE）的聚（环氧乙烷）-聚（ε-己内酯）[TPE-（PEO-PCL）]三嵌段共聚物与RhB共轭。此外，该嵌段共聚物通过一锅法嵌段共聚的简便高效合成策略获得。所得嵌段共聚物TPE-（PEO-PCL-RhB）的两亲性导致其在水性介质中自发形成胶束（BCM），并成功包封疏水性抗癌药物CHL（CHL-BCM）。对BCM和CHL-BCM的动态光散射和透射电子显微镜分析表明，其尺寸（10-100nm）有利于肿瘤组织的被动靶向——增强渗透和滞留效应。BCM的荧光发射光谱（λ 315nm）表明TPE聚集体（供体）和RhB（受体）之间存在Förster共振能量转移。另一方面，CHL-BCM显示出TPE单体发射，这可能归因于TPE和CHL分子之间的π-π堆积相互作用。药物释放曲线表明，CHL-BCM在48小时内持续释放药物。细胞毒性研究证明了BCM的生物相容性，而CHL-BCM对宫颈（HeLa）癌细胞显示出显著毒性。嵌段共聚物中RhB的固有荧光为通过共聚焦激光扫描显微镜成像直接监测胶束的细胞摄取提供了机会。这些结果证明了这些嵌段共聚物作为药物纳米载体和用于治疗诊断应用的生物成像探针的潜力。
