Dual-Layer Surface Coating of PLGA-Based Nanoparticles Provides Slow-Release Drug Delivery To Achieve Metronomic Therapy in a Paclitaxel-Resistant Murine Ovarian Cancer Model

Abstract

Development of drug resistance is a central challenge to the treatment of ovarian cancer. Metronomic chemotherapy decreases the extent of drug-free periods, thereby hindering development of drug resistance. Intraperitoneal chemotherapy allows for treatment of tumors confined within the peritoneum, but achieving sustained tumor-localized chemotherapy remains difficult. We hypothesized that modulating the surface properties of poly(lactic-co-glycolic acid) (PLGA)-based nanoparticles could enhance their drug retention ability and extend their release profile, thereby enabling metronomic, localized chemotherapy in vivo. Paclitaxel was encapsulated in particles coated with a layer of polydopamine and a subsequent layer of poly(ethylene glycol) (PEG). These particles achieved a 3.8-fold higher loading content compared to that of nanoparticles formulated from linear PLGA-PEG copolymers. In vitro release kinetic studies and in vivo drug distribution profiles demonstrate sustained release of paclitaxel. Although free drug conferred no survival advantage, low-dose intraperitoneal administration of paclitaxel-laden surface-coated nanoparticles to drug-resistant ovarian tumor-bearing mice resulted in significant survival benefits in the absence of any apparent systemic toxicity.

Clinical-grade cryopreserved doxorubicin-loaded platelets: role of cancer cells and platelet extracellular vesicles activation loop

“…The mild manufacturing process preserved the morphology and functionality of the DOXloaded PLT, as evidenced by (a) SEM observations, (b) maintained expression of important PLT markers by Western blotting, and (c) thromboelastography assay. In addition, the release kinetics of DOX from PLT in vitro was similar to that observed with artificial nanocarriers [78][79][80][81], and was significantly faster in acidic pH conditions mimicking the tumour microenvironment. The reasons for accelerated release of DOX by PLT at pH 5.5 is unclear and may involve several mechanisms.…”

Nanoparticle tumor localization, disruption of autophagosomal trafficking, and prolonged drug delivery improve survival in peritoneal mesothelioma

“…Particle-based systems are being engineered to: increase the solubility of hydrophobic drugs; provide more consistent drug levels over prolonged periods; protect sensitive drugs from degradation or enzymatic alteration; and, in some cases, provide local or “targeted” delivery to a desired tissue [19-27]. Drug delivery systems using particles, nanorods, micelles, or hydrogels, have been developed specifically for the treatment of peritoneal carcinomatoses [28-33], with poly(lactic acid) (PLA) and poly(lactic- co -glycolic acid) (PLGA) being the most widely studied formulations due to availability, biocompatibility, and use in other FDA approved devices [34-36]. Unfortunately, the rapid “burst” release of >50% of encapsulated drug within the first 10-48 hrs prevents the clinical application of these formulations in the setting of large debulking operations as post-operative healing is critical and sustained drug release is required to kill tumor cells with extended doubling times [37, 38].…”

Polydopamine Core Half-Polyamidoamine Dendrimers Based Drug-Delivery Platform and Characterization by Electrochemical Impedance Spectroscopy

“…7 Since the self-polymerization of dopamine to form surfaceadherent polydopamine (PDOA) to the surface of virtually all inorganic and organic materials was reported by Lee et al, 8 deposition of PDOA films on various materials is extensively adopted for a wide variety of functional uses. [9][10][11][12][13] Recently, novel drug-delivery systems based on PDOA 14 and its composites 15,16 have been developed, showing the promising applications of PDOA in pharmaceutical industry. Moreover, it is noteworthy that PDOA has a high density of anchoring sites (amino and imino groups), providing a versatile platform for consecutive chain-formation reactions (Michael addition reaction and amidation reaction).…”