Microneedles as Gateways: Smart Nanoparticle Delivery for Enhanced Breast Cancer Treatment

Abstract

Breast cancer is a common and potentially fatal disease caused by the abnormal proliferation of cells in the breast tissue. This outlines the critical need for early detection and awareness for effective prevention and treatment. Current therapeutic approaches for breast cancer include surgery, chemotherapy, hormonal therapy, and radiation therapy. Even with the promising strides made in breast cancer research and the inevitable advent of new treatments and drugs, achieving optimal therapeutic outcomes remains challenging due to various obstacles. Treatment with side effects is one of the greatest challenges arising from nonspecificity, with multidrug resistance demanding prolonged doses to ensure patients’ quality of life. Nanomedicine has emerged as a revolutionary approach for improving breast cancer therapy by leveraging nanoparticles for targeted drug delivery, enhanced biocompatibility and reduced systemic toxicity. Despite these advantages, nanoparticle-based therapies face challenges, including limited tumor penetration, off-target toxicity, and clinical translation barrier. To overcome these challenges, microneedle technology has been introduced as a minimally invasive, patient-friendly platform for localized drug delivery. MNs facilitate the direct transdermal administration of therapeutic agents, enhancing drug bioavailability at tumor sites while minimizing systemic side effects. The integration of NPs into MN systems represents a novel strategy to optimize cancer treatment by ensuring controlled and precise drug release. This review explores the role of nanoparticles in breast cancer therapy, the design and fabrication of MNs, and the synergies between these two technologies, while also addressing challenges in clinical translation, regulatory frameworks, and future perspectives in cancer nanomedicine.

Introduction

Breast cancer (BC) ranked in second place among diagnosed cancers worldwide in 2022. In 2024, in the United States, BC was estimated to result in 313,510 new cases, including 2790 cases in males and 310,720 cases in females. Similarly, it is associated with an estimated 42,780 deaths, comprising 530 male deaths and 42,250 female deaths (Figure 1). (1) It is the most common cancer in women and the leading cause of cancer-related mortality in 112 countries. (2,3) It is divided into three primary types: estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC). (4) Even with advances in the early detection and treatment of BC, metastasis is still the most common cause of death for patients with this disease, and the 5-year survival rate is less than 30%. The mechanism underlying metastasis is crucial to designing effective therapeutic approaches. (5) Advances achieved through surgery, radiation, chemotherapy, hormone therapy and targeted therapy greatly enhance patient outcomes. (6)

Figure 1. Estimated breast cancer cases and deaths in the United States (2024).

The BC treatment strategies are tailored to the disease stage, molecular subtype and individual patient factors. Early stage management typically involves surgery (lumpectomy or mastectomy), radiation and systemic therapies like chemotherapy or hormonal therapy, with neoadjuvant approaches increasingly used for HER2+ and TNBC. Locally advanced BC is managed with neoadjuvant chemotherapy to reduce tumor burden, followed by surgery, radiation and auxiliary node management. (7,8) Metastatic BC treatment is mainly systemic, including chemotherapy, targeted agents like trastuzumab, PARP inhibitors and CDK4/6 inhibitors; immunotherapy or hormonal therapy is given with an emphasis on palliative care for the relief of symptoms. (9) Radiation therapy has been integral in local control by including Whole Breast Radiotherapy (WBRT), Accelerated Partial Breast Irradiation (APBI) and Postmastectomy Radiation Therapy (PMRT), which are tailored by stage and risk, while Intensity-Modulated Radiation Therapy (IMRT) has allowed for reduced toxicity. (10) Precision and minimally invasive therapeutic approaches have been significantly advanced. However, challenges remain in treatment-related complications, specifically lymphedema, pneumonitis and secondary malignancies, underscoring the need for patient-specific planning and further innovation.

Nanomedicine uses nanoscale materials ranging from 1 to 100 nm in size to develop new therapeutic drugs and medical devices. The nanomaterials exhibit properties such as high surface-to-volume ratio, enhanced conductivity, supermagnetic behavior, optical absorption spectra, and characteristic fluorescence features. These characteristics allow nanomaterials to facilitate drug delivery, increase biocompatibility and transcend biological barriers. (11,12) Hence, their use in targeted cancer therapy is essential for treatment, especially since they can easily target specific biomolecules to enhance treatment efficacy without toxic effects on normal cells. Nanomedicine has advanced the treatment of BC by countering the limitations of conventional therapies. Systemic anticancer drugs, including anthracyclines and taxanes, which are typically used in chemotherapy in the late stages of BC, suffer from problems like hydrophobicity, poor targeting, and high toxicity. (13,14) Nanomedicines are revolutionizing this by protecting the drugs from being degraded in the biological environment; they improve the targeting of anticancer drugs toward cancer tissues, as well as improving biocompatibility; nanomedicine reduces the adverse effects, as well as ensures a higher drug concentration at tumor sites. In addition to that, it may target and eliminate BC stem cells, critical in the beginning of cancer, as well as the recurrence and resistance toward chemotherapy and radiotherapy. (15,16) FDA-approved and investigational nanoparticle (NP)-loaded platforms, such as liposomes and polymeric nanoparticles, have been quite promising in BC therapy. (13) These formulations bring out the advantages of nanotechnology in improving therapeutic outcomes and reducing systemic toxicity.

Although NP-based delivery systems showed great promise in improving BC therapy, their systemic delivery had challenges like limited delivery into the tumor, off-target toxicity, and patient compliance. (17) Beyond limitations, microneedle (MN) technology is emerging as a good strategy for drug delivery systems with minimized invasiveness, enabling localized dosage delivery of efficacious therapeutics while minimizing the risk of systemic side effects. For example, MN deploys chemotherapeutic agents within the skin, thus leading to a higher concentration of chemotherapeutic agents at the tumor site and lowering the requirement for high doses that could potentially cause damage to healthy tissues. (18−20) MNs can bypass the epidermal surface and reach the lymphatic capillaries; therefore, they enhance drug distribution and therapeutic benefits. Moreover, it can achieve that with minimal discomfort to the patient. MN is an ideal platform to incorporate NP-based formulations. The addition of NPs to MNs represents a novel approach toward effective therapy that minimizes side effects and ultimately optimizes patient outcomes for BC management. (21) This article reviews the invention of MNs containing NPs as a promising strategy for BC therapy that overcomes the drawbacks of current therapies. It begins with an overview of NPs in BC therapy regarding their types, mechanisms of action, and the challenges they face. It goes on to detail the design, fabrication, mechanism of release, benefits, and limitations of MN technologies, focusing specifically on their role in cancer treatment. The rationale and some of the applications of integrating NPs into the MNs are underscored with special relevance to their use as therapeutic vehicles; the problems translating to the clinic in future, biocompatibility, and regulatory challenges were discussed. This review uniquely consolidates current advancements in NP-integrated MN systems for breast cancer therapy, offering a comprehensive perspective on their design, therapeutic mechanisms and translational challenges, making it an innovative contribution to evaluate this emerging interdisciplinary strategy.

The various types of nanoparticles employed for BC therapy, including polymeric nanoparticles, solid lipid nanocarriers, nanostructured lipid carriers, mesoporous silica nanoparticles, and gold nanoparticles, have been studied (Supporting Information, Section S1, Figure S1).

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Microneedles as Gateways: Smart Nanoparticle Delivery for Enhanced Breast Cancer Treatment, Viola Colaco, Deepanjan Datta, Ritu Kudarha, Abhishek Kumar Singh, and Namdev Dhas, ACS Omega Article ASAP, DOI: 10.1021/acsomega.5c04565