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Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

ABSTRACT: Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release, targeted drug delivery, post-surgery implants (immunovaccines), theranostics, biosensing of tumor-derived circulating materials, multimodal systems, and combination therapy platforms with the potential to eliminate bulk tumors as well as lingering tumor cells to treat minimal residual disease (MRD) and recurrent cancer. We first introduce different formats, derivatives, and properties of chitosan. Next, given the barriers to therapeutic efficacy in solid tumors, we review advanced formulations of chitosan modules as efficient drug delivery systems to overcome tumor heterogeneity, multi-drug resistance, MRD, and metastasis. Finally, we discuss chitosan NPs for clinical translation and treatment of recurrent cancer and their future perspective.

SUBMITTER: Mahmudi H

PROVIDER: S-EPMC9751059 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Mahmudi Hossein H Adili-Aghdam Mohammad Amin MA Shahpouri Mohammad M Jaymand Mehdi M Amoozgar Zohreh Z Jahanban-Esfahlan Rana R

Frontiers in oncology 20221130

Chitosan and its derivatives are among biomaterials with numerous medical applications, especially in cancer. Chitosan is amenable to forming innumerable shapes such as micelles, niosomes, hydrogels, nanoparticles, and scaffolds, among others. Chitosan derivatives can also bring unprecedented potential to cross numerous biological barriers. Combined with other biomaterials, hybrid and multitasking chitosan-based systems can be realized for many applications. These include controlled drug release ...[more]

PMID: 36531004

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Project description:BackgroundCurrent surveillance modalities of osteosarcoma relapse exhibit limited sensitivity and specificity. Although circulating tumor DNA (ctDNA) has been established as a biomarker of minimal residual disease (MRD) in many solid tumors, a sensitive ctDNA detection technique has not been thoroughly explored for longitudinal MRD detection in osteosarcoma.MethodsFrom August 2019 to June 2023, 59 patients diagnosed with osteosarcoma at the First Affiliated Hospital of Sun Yat-sen University were evaluated in this study. Tumor-informed MRD panels were developed through whole exome sequencing (WES) of tumor tissues. Longitudinal blood samples were collected during treatment and subjected to multiplex PCR-based next-generation sequencing (NGS). Kaplan-Meier curves and Log-rank tests were used to compare outcomes, and Cox regression analysis was performed to identify prognostic factors.FindingsWES analysis of 83 patients revealed substantial mutational heterogeneity, with non-recurrent mutated genes accounting for 58.1%. Tumor-informed MRD panels were successfully obtained for 85.5% of patients (71/83). Among 59 patients with successful MRD panel customization and available blood samples, 13 patients exhibited positive ctDNA detection after surgery. Patients with negative post-operative ctDNA had better event-free survival (EFS) compared to those with positive ctDNA, at 1-6 months after surgery, after adjuvant chemotherapy, and more than 6 months after surgery (p < 0.05). In both univariate and multivariate Cox regression analysis, ctDNA results emerged as a significant predictor of EFS (p < 0.05). ctDNA detection preceded positive imaging in 5 patients, with an average lead time of 92.6 days. Thirty-nine patients remained disease-free, with ctDNA results consistently negative or turning negative during follow-up.InterpretationOur study underscores the applicability of tumor-informed deep sequencing of ctDNA in osteosarcoma MRD surveillance and, to our knowledge, represents the largest cohort to date. ctDNA detection is a significant prognostic factor, enabling the early identification of tumor relapse and progression compared to standard imaging, thus offering valuable insights in guiding osteosarcoma patient management.FundingThe Grants of National Natural Science Foundation of China (No. 82072964, 82072965, 82203798, 82203026), the Natural Science Foundation of Guangdong (No. 2023A1515012659, 2023A1515010302), and the Regional Combination Project of Basic and Applied Basic Research Foundation of Guangdong (No. 2020A1515110010).

Project description:BackgroundMinimal residual disease (MRD) is considered an essential factor leading to relapse within 2 years (early relapse) after radical surgery, which is challenging to be detected by conventional imaging. Circulating tumor DNA (ctDNA) provides a novel approach for detecting MRD and predicting clinical outcomes. Here, we tried to construct a fixed panel for plasma-only ctDNA NGS to enable tumor-uninformed MRD detection in hepatocellular carcinoma (HCC).MethodsHere, we performed the followings: (i) profiling genomic alteration spectrum of ctDNA from the Chinese HCC cohort consisting of 493 individuals by NGS; (ii) screening of MRD monitoring genes; and (iii) performance evaluation of MRD monitoring genes in predicting early relapse in the ZJZS2020 cohort comprising 20 HCC patients who underwent curative resection.ResultsA total of 493 plasma samples from the Chinese HCC cohort were detected using a 381/733-gene NGS panel to characterize the mutational spectrum of ctDNA. Most patients (94.1%, 464/493) had at least one mutation in ctDNA. The variants fell most frequently in TP53 (45.1%), LRP1B (20.2%), TERT (20.2%), FAT1 (16.2%), and CTNNB1 (13.4%). By customized filtering strategy, 13 MRD monitoring genes were identified, and any plasma sample with one or more MRD monitoring gene mutations was considered MRD-positive. In the ZJZS2020 cohort, MRD positivity presented a sensitivity of 75% (6/8) and a specificity of 100% (6/6) in identifying early postoperative relapse. The Kaplan-Meier analysis revealed a significantly short relapse-free survival (RFS; median RFS, 4.2 months vs. NR, P=0.002) in the MRD-positive patients versus those with MRD negativity. Cox regression analyses revealed MRD positivity as an independent predictor of poor RFS (HR 13.00, 95% CI 2.60-69.00, P=0.002).ConclusionsWe successfully developed a 13-gene panel for plasma-only MRD detection, which was effective and convenient for predicting the risk of early postoperative relapse in HCC.

Dataset Information

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

Publications

Tumor microenvironment penetrating chitosan nanoparticles for elimination of cancer relapse and minimal residual disease.

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