Anggraini Ihza Rizkita, Assyfa Atha, Dafina Aisya Fitri
@Anggraini @Assyfa Atha @Dafina

ABSTRACT
Radiopharmaceutical therapy (RPT) is one of the promising treatments for breast cancer. However, most RPT administrations still utilize the invasive intravenous (IV) route, which requires specialized expertise. In comparison, the topical route is more accessible. Nevertheless, some topical dosage forms do not give precise dose uniformity. There is a suitable isotope and the right microneedle patch material to obtain a significant therapeutic effect and a dosage form that helps the therapeutic process. Therefore, this narrative review is designed to examine strategies and uncover the potential utilization of radioactive substances in the form of microneedle patches for treating breast cancer. Some keywords were used to search for literature from journal databases like Google Scholar, PubMed, ScienceDirect, Scopus, and Elsevier. There are some potential isotopes, 227-Th, 177-Lu, and 223-Ra. We established some criteria for the desired radioisotope, and the one that provides the best criteria is 227-Th due to its ability to induce cytotoxic effects in HER2-expressing breast cancer cell lines. The criteria for the desired material for the microneedle patch are non-toxic and able to maintain radioisotope stability well. PVA/PVP is the one that provided the best criteria for material due to its ability to maintain the stability of radioisotope and non-toxicity, resistance to most acids and alkalis, and high electrical insulation. The conclusion is that 227-Th is the most potential radioisotope for topical breast cancer treatment, and PVA/PVP is the most potential material for microneedle patches for radiopharmaceutical dosage forms. All the reviews aim to be a starting point for future research in developing radioisotope therapy for cancer treatment in topical microneedle patch dosage form.
Keywords: Radioisotope, Breast Cancer, Microneedle, Topical Patch

INTRODUCTION
Breast cancer treatment is complex, but topical treatments are emerging as a promising tool. Surgery, radiation, and various medications are traditionally used to fight the disease. However, research suggests topical treatments applied directly to the skin might play a significant role in the future (Beck et al., 2022; Lee, 2023). Topical treatments offer several potential benefits. They could deliver medication specifically to breast tissue, potentially making them more effective and safer than traditional therapies. This approach has also shown promise in treating skin cancer, offering a non-invasive option with fewer side effects than some medications (Cullen et al., 2020; Kim et al., 2023; Rath et al., 2023). The skin naturally acts as a barrier, limiting the medication's ability to reach the targeted area. That barrier becomes a challenge for the drug delivery system. Researchers are developing drugs to overcome that challenge, using unique ingredients to enhance absorption and even employing tiny carrier systems.
Radiopharmaceutical Therapy (RPT) emerges as a promising avenue, offering effectiveness and safety. This innovative approach delivers a potent dose directly to the cancerous tissue while sparing surrounding healthy cells from harm. RPT showcases advantages over traditional treatment methods by utilizing radioactive atoms bound to specific tumor-targeting molecules such as antibodies and peptides. Its potential in breast cancer therapy shines through, offering hope for improved outcomes. Alongside RPT, radiotherapy is pivotal in the treatment landscape, contributing to high disease control rates and patient survival. Embraced as part of a comprehensive treatment regimen, radiotherapy stands as a cornerstone in the therapeutic triad for breast cancer patients. Furthermore, considering the administration of radiotherapy before surgery could amplify its effectiveness, potentially enabling less invasive procedures and ultimately enhancing both disease-free and overall survival rates.
RPT as a treatment for breast cancer is deemed "greener" due to its minimal environmental impact. Additionally, RPT usage can enhance the accuracy of breast cancer diagnosis, staging, and monitoring, promising a personalized treatment approach (Salih et al., 2022). However, most RPT administrations still utilize the invasive intravenous (IV) route, requiring specialized expertise. In comparison, topical administration would be easier for patients to apply. Thus, the innovation of topical RPT poses an intriguing challenge and holds the potential to offer more efficient, better, and easier cancer treatment.
Nevertheless, there are several issues in the development of topical RPT. Typically, topical formulations like ointments, such as tamoxifen, cannot ensure precise dose uniformity upon application. A formulation allowing for controlled drug release with equivalent dosing is the patch with microneedle innovations (MPs). MPs are minimally invasive, painless, and user-friendly, making them appealing for biomedical applications. They have demonstrated efficient drug and vaccine delivery into the skin, providing a painless and convenient administration route. Research indicates that MPs are well-tolerated, user-friendly, and highly accepted by human subjects, facilitating further clinical translation. The design of MP patches should enable the maintenance of radioactive compound levels, prevent skin irritation, and ensure continuous drug release at predetermined doses (Arya et al., 2017; Prausnitz, 2017; Li et al., 2017; Ripolin et al., 2017; Pan et al., 2022). Therefore, this narrative review is designed to examine strategies and uncover the potential utilization of radioactive substances in the form of microneedle patches for treating breast cancer.
DISCUSSION
Radioisotopes for topical patch-based microneedle delivery in breast cancer treatment require specific criteria to meet therapeutic needs. We established criteria for the desired radioisotope, including a half-life between 7-30 days, a specific mechanism for breast cancer treatment, and a clear mechanism of action for controlled use. Table 1 presents several potential isotopes identified in our search.

Table 1. List of Potential Isotopes for Breast Cancer Treatment in Topical Patch Microneedle Pharmaceutical Dosage Form. The table available in the link below :
https://bit.ly/Table1_ListofPotentialIsotopesforBreastCancerTreatmentinTopicalPatchMicroneedlePharmaceuticalDosageForm

Conventionally, drugs were delivered via the parenteral route by syringe and a hypodermic needle. Although the parenteral routes are more affordable, this technique can cause discomfort to the patient, including excruciating pain, thrombus formation at the site of injection, and hypersensitivity. Researchers focused on developing a novel drug delivery method known as the "Transdermal Drug Delivery System" (TDDS) using microneedle, which helps transfer the medications via the layers of skin, in order to address the drawbacks of oral and parenteral modes of administration of good vasculature in the dermis, the layer of skin beneath the epidermis, aids in the absorption of medications. The epidermis, or "stratum corneum (SC)," the outermost layer of skin, serves as the primary barrier against TDDS. The medicine was made to migrate across the SC using several techniques and strategies. To enhance drug delivery, multiple techniques were implemented to facilitate drug transportation throughout the SC. When anticancer medications are administered to patients parenterally, they frequently accumulate in many organs and have low bioavailability because of their rapid excretion from the bloodstream, which reduces their therapeutic efficiency to enhance the efficacy of the drug cancer microneedle can contribute to the appropriate outcome. It will be regarded as a synergistic microneedle administration to enhance the easy, non-invasive, and safer substitutes for specific delivery, help prevent the death of cells, avoid side effects, and maintain the safety for undergoing radiotherapy (Seetharam et al., 2020).
FDA gives strict regulatory requirements for medical devices and products. Microneedle materials are selected to ensure biocompatibility, safety, and stability to fulfill the requirements of the FDA. Meanwhile, microneedle materials must be safe and support the effectiveness of radioisotopes in achieving therapeutic targets. Therefore, the following summarizes the microneedle material-based polymers due to the polymer's easy formability, short processing cycle, low cost, and rich material variety; it is the ease of achieving large-scale production and needle-good toughness. Polymers are safe for the environment due to the polymer being biocompatible and biodegradable. Based on the table below, PVA/PVP is a promising material as a microneedle due to its characteristic ability to maintain the stability of radioisotope and non-toxicity, resistance to most acids and alkalis, and high electrical insulation.
Tabel 2. List of Potential Materials for Topical Patch Microneedle. The table available in the link below :
https://bit.ly/ListofPotentialMaterialsforTopicalPatchMicroneedle

Approximately 25-30% of breast cancers overexpress Human Epidermal Growth Factor Receptor-2 (HER-2). The existence of intrinsic and acquired resistance to antibodies targeting HER2 or antibody-drug conjugates (ADCs) means that developing new, more effective therapies is needed. The radioisotope 227-Th co-labeled with trastuzumab to become 227Th-trastuzumab shows significant anti-tumor effects against breast cancer expressing HER-2 as it induces cytotoxic effects in breast cancer cell lines expressing HER-2 (Karlsson et al., 2023). Moreover, apart from HER-2, Fibroblast Growth Factor Receptor 2 (FGFR2), which is commonly associated with aggressive cancer phenotypes, such as breast cancer, can also be a therapeutic target by 227Th-trastuzumab.
Radiopharmaceutical therapy (RCT) commonly uses an invasive IV route administration to treat targeted cancer. However, topical innovation of drug administration, utilizing microneedle through transdermal drug delivery, shows a considerable amount of potential and benefits. In addition, microneedle innovation (MPs) is suitable for breast cancer treatment as it allows the delivery of large molecules, high drug bioavailability, controlled dose therapy, and localized drug delivery (Jung & Jin, 2021). Therefore, it is very favorable to use MPs to deliver 227Th-trastuzumab in breast cancer treatment. The material of microneedles that will be used for breast cancer therapy with 227Th-trastuzumab is GelMa.

CONCLUSION
Isotope 227-Thorium labeld trastuzumab is suitable as a therapy for breast cancer that express HER-2 andFGFR2. Moreover, breast cancer treatment in topical administration use microneedle is more potential and beneficial compared to conventional IV or topical treatment. The type of suitable microneedle material for 227Th-trastuzumab is PVA/PVP due to its characteristic which able to maintain the stability of radioisotope and non-toxicity, resistance to most acids and alkalis, and a high electrical insulation. All of review aim to be starting point for future research in developing radioisotope therapy for cancer treatment in topical microneedle patch dosage form.

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