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Primary adipocytes as targetable drug depot to prevent post-surgical cancer recurrence.

ABSTRACT: Surgery followed by adjuvant chemotherapy or radiation therapy remains the mainstream treatment for breast cancer in the clinic. However, cancer recurrence post surgery is still common. In view of the clinical practice that autologous fat tissue grafting is often used to facilitate breast reconstruction after lumpectomy, here we develop an in vivo targetable adipocyte-based drug depot for the prevention of post-surgical cancer recurrence. We show that primary adipocytes can be metabolically labeled with clickable chemical tags (e.g., azido groups), for subsequent conjugation of dibenzocyclooctyne (DBCO)-bearing cargo via efficient click chemistry. The conjugated cargo can retain well on the adipocyte membrane. By incorporating a cleavable linker between DBCO and cargo, the conjugated cargo can be gradually released from the surface of adipocytes to effect on neighboring cells. In the context of breast cancer surgery, azido-labeled adipocytes grafted to the surgical site can capture circulating DBCO-drugs for improved prevention of 4T1 triple-negative breast cancer (TNBC) recurrence and metastasis. This targetable and refillable adipocyte-based drug depot holds great promise for drug delivery, transplantation, and other applications.

SUBMITTER: Bo Y

PROVIDER: S-EPMC10945205 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Primary adipocytes as targetable drug depot to prevent post-surgical cancer recurrence.

Bo Yang Y Wang Yueji Y Han Joonsu J Bhatta Rimsha R Liu Yusheng Y Baskaran Dhyanesh D Zhou Jiadiao J Wang Hua H

Materials today. Bio 20240307

Surgery followed by adjuvant chemotherapy or radiation therapy remains the mainstream treatment for breast cancer in the clinic. However, cancer recurrence post surgery is still common. In view of the clinical practice that autologous fat tissue grafting is often used to facilitate breast reconstruction after lumpectomy, here we develop an <i>in vivo</i> targetable adipocyte-based drug depot for the prevention of post-surgical cancer recurrence. We show that primary adipocytes can be metabolical ...[more]

PMID: 38500558

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Project description:PurposeThe brain, protected by the cranium externally and the blood-brain barrier (BBB) internally, poses challenges in chemotherapy of aggressive brain tumors. Maximal tumor resection followed by radiation and chemotherapy is the standard treatment protocol; however, a substantial number of patients suffer from recurrence. Systemic circulation of drugs causes myelodysplasia and other side effects. To address these caveats, we report facile synthesis of a polyester-based supramolecular hydrogel as a brain biocompatible implant for in situ delivery of hydrophobic drugs.MethodsPolycaprolactone-diol (PCL) was linked to polyethyleneglycol-diacid (PEG) via an ester bond. In silico modeling indicated micelle-based aggregation of PCL-PEG co-polymer to form a supramolecular hydrogel. Brain biocompatibility was checked in Sprague Dawley rat brain cortex with MRI, motor function test, and histology. Model hydrophobic drugs carmustine and curcumin entrapment propelled glioma cells into apoptosis-based death evaluated by in vitro cytotoxicity assays and Western blot. In vivo post-surgical xenograft glioma model was developed in NOD-SCID mice and evaluated for efficacy to restrict aggressive regrowth of tumors.Results20% (w/v) PCL-PEG forms a soft hydrogel that can cover the uneven and large surface area of a tumor resection cavity and maintain brain density. The PCL-PEG hydrogel was biocompatible, and well-tolerated upon implantation in rat brain cortex, for a study period of 12 weeks. We report for the first time the combination of carmustine and curcumin entrapped as model hydrophobic drugs, increasing their bioavailability and yielding synergistic apoptotic effect on glioma cells. Further in vivo study indicated PCL-PEG hydrogel with a dual cargo of carmustine and curcumin restricted aggressive regrowth post-resection significantly compared with control and animals with intravenous drug treatment.ConclusionPCL-PEG soft gel-based implant is malleable compared with rigid wafers used as implants, thus providing larger surface area contact. This stable, biocompatible, supramolecular gel without external crosslinking can find wide applications by interchanging formulation of various hydrophobic drugs to ensure and increase site-specific delivery, avoiding systemic circulation.

Project description:ImportanceDespite widespread recognition and known harms, serious surgical errors, known as surgical never events, endure. The California Department of Public Health (CDPH) has developed an oversight system to capture never events and a platform for process improvement that has not yet been critically appraised.ObjectivesTo examine surgical never events occurring in hospitals in California and summarize recommendations to prevent future events.Design, setting, and participantsThis cross-sectional study identified 386 CDPH hospital administrative penalty reports, of which 142 were ascribable to never events occurring during surgery. These never events were identified and summarized from January 1, 2007, to December 31, 2017. A directed qualitative approach was used to analyze CDPH-mandated corrective steps to reduce future errors in this multicenter study of all accredited hospitals in California. Inclusion of surgical never event records was based on definitions established by the US Department of Health and Human Services National Quality Forum. Data analysis was performed from January 1, 2019, to November 30, 2020.ExposuresNever events include death or disability of an American Society of Anesthesiologists class I patient, wrong site or wrong surgery, retained foreign objects, burns, equipment failure leading to intraoperative injury, nonapproved experimental procedures, insufficient surgeon presence or privileges, or fall from the operating room table.Main outcomes and measuresIncident rates, consequences, and improvement plans to prevent additional never events were outcomes of interest.ResultsA total of 142 never events were reported to the CDPH (1 per 200 000 operations). Annual surgical volume for hospitals with events was 9203 vs 3251 cases for hospitals without events (P < .001). A total of 94 of 142 events (66.2%) were retained foreign objects ranging from Kocher clamps to drain sponges. Wrong site or patient surgery accounted for 22 events (15.5%), surgical burns for 11 (7.7%), and other for 15 (10.6%). Other included insufficient surgeon presence, equipment failure, or falls in the operating room. Improvement plans included 18 unique categories of recommendations from regulators, many focusing on proper use of checklists. Regulators mandated a mean (SD) of 13 (7) corrective actions in the improvement plans. Policy adherence monitoring (119 [90.2%]), revision of existing policy (84 [63.6%]), and education regarding policy (83 [62.9%]) were common action items, whereas disciplinary action toward staff was rare (11 [8.3%]).Conclusions and relevanceSurgical never events are a rare issue in California. Numerous strategies have evolved to reduce errors, many involving the thorough and proper use of intraoperative checklists.

Project description:Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P < 0.20). A total of 551 microRNAs and 2486 messenger RNAs were associated with clusters A1 and B4, respectively (adjusted P < 0.05). Clustering of brain-tissue messenger RNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated messenger RNA transcripts with cluster B4. Clusters A1, B4 and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which microRNA and messenger RNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4 and C2 reveal both known and novel microRNA and messenger RNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples and could potentially serve as biomarkers for surgical resection outcomes.

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Primary adipocytes as targetable drug depot to prevent post-surgical cancer recurrence.

Publications

Primary adipocytes as targetable drug depot to prevent post-surgical cancer recurrence.

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