TMTP1-Modified, Tumor Microenvironment Responsive Nanoparticles Co-Deliver Cisplatin and Paclitaxel Prodrugs for Effective Cervical Cancer Therapy

Abstract

Background and Purpose Cisplatin–paclitaxel (TP) combination chemotherapy as the first-line therapy for numerous cancers is hindered by its inadequate accumulation in tumors and severe side effects resulting from non-specific distribution. The aim of this study is to explore whether TMTP1-modified, cisplatin and paclitaxel prodrugs co-loaded nanodrug could improve cervical cancer chemotherapy and relieve its side effects through active and passive tumor targeting accumulation and controlled drug release. Methods TDNP, with capacities of active targeting for tumors and controlled drug release, was prepared to co-deliver cisplatin and paclitaxel prodrugs. The characteristics were investigated, including the diameter, surface zeta potential, stability and tumor microenvironment (TME) dependent drug release profiles. Cellular uptake, cytotoxicity, drug accumulation in tumors, antitumor effects and safety analysis were evaluated in vitro and in vivo. Results The oxidized cisplatin and the paclitaxel linked to the polymer achieved a high loading effciency of over 80% and TME-dependent sustained drug release. Moreover, TMTP1 modification enhanced cellular uptake of TDNP and further improved the cytotoxicity of TDNP in vitro. In vivo, TDNP showed an extended blood circulation and increased accumulation in SiHa xenograft models with the aid of TMTP1. More importantly, TDNP controlled tumor growth without life-threatening side effects. Conclusion Our study provided a novel TP co-delivery platform for targeted chemotherapy of cervical cancer, which was promising to improve the therapeutic effcacy of TP and may also have application in other tumors.

Responsive polyprodrug for anticancer nanocarriers

“…The low drug release at low concentration of GSH could presumably prevent the release of Pt from NPs during circulation in plasma or extracellular fluid. For comparison, ∼20% Pt-drug was released after 48 h from nanoparticles without GSH while ∼60% Pt-drug was released in the presence of 10 mM of GSH, 38,40 indicating that FA-DSS-Pt(dach)Cl 2 NPs displayed an excellent selectivity of drug release. In addition, the release of Pt(dach)Cl 2 from nanoparticles was investigated after incubation of the nanoparticles in 10 mM GSH at 37 °C for 72 h. The release media was lyophilized and dissolved in DMSO-d 6 for 1 H and 13 C NMR spectroscopy measurements to confirm the release of Pt(dach)Cl 2 .…”

“…Therefore, glutathione (GSH)-responsive NPs were prepared for the triggered release of Pt-based drugs in tumor cells. 36–41 Several groups reported the fabrication of nanoparticles containing Pt( iv ) prodrugs which produced active responsive Pt( iv ) prodrugs were encapsulated in nanoparticles 36–38 or conjugated with polymers via click reactions, 39 esterification, 40 or an amidation. 41 Some current limitations include low Pt loading, 38–41 or low Pt release.…”

“…36–41 Several groups reported the fabrication of nanoparticles containing Pt( iv ) prodrugs which produced active responsive Pt( iv ) prodrugs were encapsulated in nanoparticles 36–38 or conjugated with polymers via click reactions, 39 esterification, 40 or an amidation. 41 Some current limitations include low Pt loading, 38–41 or low Pt release. 38,40 Furthermore, a random conjugation of drugs in the side chain of polymers can provide batch-to-batch variations of drug loading and release profiles, which can be an obstacle to clinical translation.…”

“…41 Some current limitations include low Pt loading, 38–41 or low Pt release. 38,40 Furthermore, a random conjugation of drugs in the side chain of polymers can provide batch-to-batch variations of drug loading and release profiles, which can be an obstacle to clinical translation. 42,43 Polyprodrugs are produced by polymerizing drugs bonded in the polymer chain with stimuli-responsive linkers.…”

Comprehensive Expression Profiling and Molecular Basis of CDC28 Protein Kinase Regulatory Subunit 2 in Cervical Cancer

“…Multiple factors, such as premature sexual behavior, multiple personality partners, early marriage and early childbirth, multiple childbirth, smoking, and HIV infection, could raise the risk of cervical cancer [ 4 ]. Significant advances have been made in screening tests and treatment strategies, including chemotherapy and radiotherapy [ 5 , 6 ]. An increasing amount of evidence suggests the benefits of the clinical application of a multidisciplinary approach to the management of female tumors, which helps improve the quality of life of patients [ 7 – 9 ].…”