A nano drug delivery system can transport anticancer agents and preferentially reach tumor sites, owing to the advantages of reduced clearance from the reticuloendothelial system (RES), increased tumor accumulation through enhanced permeation and retention (EPR), and effective cellular uptake, as they offer a less invasive alternative compared with conventional therapeutic cocktails (e.g., chemotherapy, radiation therapy, and surgery), thereby minimizing the excessive toxic side effects and maximizing the efficacy of drugs in clinical trials[1, 2]. Some characteristics can be the prerequisites for a nano drug delivery system: (1) a low cytotoxicity and the possibility of biodegradability of the vector itself, (2) versatile surface functionalization, (3) a high drug-loaded content related with elevated therapeutic efficacy, (4) a good dispersibility and colloidal stability of the vector in physiological conditions, (5) a low level of protein adsorption related with a prolonged circulation time, (6) a low degree of premature leakage and the possibility for controlled release of drugs, and (7) can be targeted to cell/tissue of choice and effective cellular uptake[3–5].
Self-assembled nanoparticles (NPs) have attracted considerable interest for their potential use in drug delivery and cancer therapy since they can encapsulate a series of poorly water-soluble anticancer drugs and release them in a sustained manner at their target site[6–8]. Self-assembly technique can provide a simple and low-cost method for producing NPs in a controllable way. Polymeric amphiphiles consisting of hydrophilic and hydrophobic parts can form nanosized self-assemblies with a hydrophobic core and a hydrophilic shell. The hydrophilic shell contributes to their prolonged circulation to increase their ability of reaching the target tumor tissue after systemic administration in vivo. More importantly, because of their abnormally leaky vasculature and lack of an effective lymphatic drainage system, self-assembled NPs also tend to be accumulated in tumor sites.
Paclitaxel (PTX), one of the most exciting anticancer agents, was currently available. It showed effective activity by inhibiting various tumors and had been used clinically in the treatment of metastatic breast cancer, ovarian cancer, and several other malignancies. New research has shown that PTX has antiangiogenic activity by inhibiting vascular endothelial cell proliferation, motility, and cord/tube formation at extremely low concentrations. For these reasons, we chose PTX as the model chemotherapeutic agent. Despite its potent anticancer activity, unfortunately limited by poor water solubility and toxic side effects, it has no great advantage in tumor targeting for drug delivery and cancer therapy.
A series of efforts has been directed to the development of alternative delivery systems for PTX. Poly(d,l-lactide) (PLA), a FDA-approved biodegradable and non-cytotoxic material with a good track record in offering great potential for controlled release, has stood out and been extensively used in the formulation of NPs for biotechnology and drug delivery applications. However, in aqueous solution, the drug-loaded PLA NPs presented poor dispersibility and colloidal stability; in addition, the PLA NPs were not amenable to rapid clearance from the circulation by the RES, immediately after their injection into the systemic circulation. A safe and effective way to answer this problem is to design long-circulating NPs with hydrophilic polymers. Polyethylene glycol (PEG), also a FDA-approved polymer highly soluble in water, has been widely used as a long-circulating agent to improve the biocompatibility and increase the colloidal stability of NPs through steric hindrance, which was often incorporated in drug carriers for delivery to the human body, according to its resistance against opsonization, the process through which protein adsorption is enhanced to induce phagocytosis[15–17]. Thereby, methoxypolyethylene glycol-poly(d,l-lactide) (MPEG-PLA) diblock copolymers have been of great interest as a completely biocompatible material for drug delivery[18, 19]. Moreover, MPEG-PLA could make long circulation possible for pharmaceutical uses and opened new perspectives for controlled drug delivery in particular.
In this paper, we present a dialysis technique to direct the self-assembly of PTX-loaded NPs using MPEG-PLA diblock copolymers and PLA, respectively. The hydrophobic polymeric core of the platform readily encapsulated the water-insoluble drug for systemic delivery. The physicochemical properties of the PTX-MPEG-PLA NPs were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), dynamic light scattering (DLS), static light scattering (SLS), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM). In vitro drug release profiles and cytotoxicity tests were also conducted. The PTX-PLA NPs were also prepared and characterized in the same way and used for comparison.