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Charge and Size Dual Switchable Nanocage for Novel Triple?Interlocked Combination Therapy Pattern

ABSTRACT: Abstract Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH?triggered charge and size dual switchable nanocage co?loaded with abemaciclib and IMD?0354 (PA/PI?ND) is reported, exhibiting a novel triple?interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR?poly(ethylene glycol)?poly(l?lysine)?dimethylmaleic anhydride (NGR?PEG?PLL?DMA, ND) in PA/PI?ND promotes the pH?triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI?ND triple?interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD?0354. The dual anti?tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD?0354 promoting tumor?associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI?ND has improved anti?tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI?ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy. PA/PI?ND can deliver to tumor tissues mediated by active ligand NGR. The interior PA and PI is released because of the switch of charge and size at the acidic tumor microenvironment to promote cellular uptake and deep penetration. PA/PI?ND also pocesses a triple?interlocked combination therapy pattern of chemotherapy, immunotherapy, and chemoimmunotherapy.

SUBMITTER: Yang R

PROVIDER: S-EPMC7509747 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:IntroductionIn the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI or UMEC/VI dual therapy in patients with chronic obstructive pulmonary disease (COPD); however, pneumonia incidence was higher in FF-containing arms. As COPD is a growing problem in Asia, we compared the efficacy and safety of FF/UMEC/VI in Asia versus non-Asia regions.MethodsIMPACT was a double-blind, 52-week trial in symptomatic COPD patients with ≥ 1 moderate/severe exacerbation in the prior year. This pre-specified analysis evaluated the annual rate of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score, mortality, and safety (including pneumonia) in Asia versus non-Asia regions.ResultsThe intent-to-treat population comprised 10,355 patients (Asia n = 1644 [16%]). Rate ratios (95% confidence intervals) for moderate/severe exacerbations with FF/UMEC/VI were 0.89 (0.76-1.05) versus FF/VI and 0.86 (0.71-1.04) versus UMEC/VI in Asia, and 0.84 (0.79-0.90) and 0.74 (0.68-0.80) in non-Asia. Efficacy of FF/UMEC/VI on other endpoints was similar in both regions. There was an increased incidence of investigator-reported pneumonia in patients in Asia (FF/UMEC/VI: 13%; FF/VI: 14%; UMEC/VI: 6%) compared with non-Asia (FF/UMEC/VI: 6%; FF/VI: 5%; UMEC/VI: 4%). The increased risk of pneumonia in patients in Asia was most marked in patients with lower body mass index, lower lung function, and taking inhaled corticosteroids. In post hoc analysis of adjudicated on-treatment all-cause mortality, probabilities of death were numerically lower in both regions with FF/UMEC/VI (Asia: 1.16%; non-Asia: 1.35%) and FF/VI (Asia: 1.77%; non-Asia: 1.21%) versus UMEC/VI (Asia: 1.91%; non-Asia: 2.23%).ConclusionsFF/UMEC/VI provides similar benefits in COPD patients in Asia and non-Asia regions. Clinical benefits of treatment, including reduction in mortality risk, should be weighed against risk of pneumonia, taking account of all known risk factors.Trial registrationClinicalTrials.gov identification, NCT02164513.

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Charge and Size Dual Switchable Nanocage for Novel Triple?Interlocked Combination Therapy Pattern

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