Investigation of a Dual siRNA/Chemotherapy Delivery System for Breast Cancer Therapy
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ABSTRACT:
SUBMITTER: Zhao Y
PROVIDER: S-EPMC9134248 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Project description:ObjectiveAlthough great progress has been made in the field of siRNA gene therapy, safe, efficient, and targeted delivery of siRNA are still major challenges in siRNA therapeutics.MethodsWe developed an up-conversion nanoparticle-based nanocage system. This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites, due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.ResultsThe siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites, where they accumulated. Compared with the passive target and control groups, the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.ConclusionsThe up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites. Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes, high tumor inhibition ratios, and longer survival times.
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Project description:RNA interference holds the promise to knock down expression of every cancer gene. Both academic laboratories and pharmaceutical companies have committed heavily on manpower and financial resources to develop small interfering RNA (siRNA) cancer therapeutics over the last decade. Although significant advances have been made in the design of siRNA therapeutics and mechanism of action on cancer cell killing, there are still many hurdles to overcome including effective delivery of therapeutics in vivo. Nanotechnology has had an important role in the development of delivery vectors so far. This article summarizes current nanovectors for siRNA delivery, discusses technical challenges in overcoming biological barriers, and introduces the multistage vector system for tumor-specific delivery.
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Project description:This study involves the fabrication and characterization of a multifunctional therapeutic nanocomposite system, as well as an assessment of its in vitro efficacy for breast cancer treatment. The nanocomposite system combines gold nanorods (GNRs) and gold nanoclusters (GNCs) to enable a combination of photothermal therapy and doxorubicin-based chemotherapy. GNRs of various sizes but exhibiting similar absorbance spectra were synthesized and screened for photothermal efficiency. GNRs exhibiting the highest photothermal efficiency were selected for further experiments. GNCs were synthesized in bovine serum albumin (BSA) and integrated into citrate-capped GNRs using layer-by-layer assembly. Glutaraldehyde crosslinking with the lysine residues in BSA was employed to immobilize the GNCs onto the GNRs, forming a stable "soft gel-like" structure. This structure provided binding sites for doxorubicin through electrostatic interactions and enhanced the overall structural stability of the nanocomposite. Additionally, the presence of GNCs allowed the nanocomposite system to emit robust fluorescence in the range of ~520 nm to 700 nm for self-detection. Hyaluronic acid was functionalized on the exterior surface of the nanocomposite as a targeting moiety for CD44 to improve the cellular internalization and specificity for breast cancer cells. The developed nanocomposite system demonstrated good stability in vitro and exhibited a pH- and near-infrared-responsive drug release behavior. In vitro studies showed the efficient internalization of the nanocomposite system and reduced cellular viability following NIR irradiation in MDA-MB-231 breast cancer cells. Together, these results highlight the potential of this nanocomposite system for targeted breast cancer therapy.
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Project description:PurposeMost cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear.MethodsIn 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy.ResultsOverall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years.ConclusionResults offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.
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Project description:RNA interference (RNAi) is a gene regulation mechanism initiated by RNA molecules that enables sequence-specific gene silencing by promoting degradation of specific mRNAs. Molecular therapy using small interfering RNA (siRNA) has shown great therapeutic potential for diseases caused by abnormal gene overexpression or mutation. The major challenges to application of siRNA therapeutics include the stability and effective delivery of siRNA in vivo. Important progress in nanotechnology has led to the development of efficient siRNA delivery systems. In this review, the authors discuss recent advances in nanoparticle-mediated siRNA delivery and the application of siRNA in clinical trials for cancer therapy. This review will also offer perspectives on future applications of siRNA therapeutics.
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