Solid lipid nanoparticles in cervical cancer: a comprehensive review of a decade of progress and prospects

Abstract

Background: Cervical cancer is the second most commonly diagnosed cancer worldwide and the third leading cause of death among women, with approximately 604 127 new cases being reported in 2020. Conventional treatment methods, such as chemotherapy, radiation therapy, surgery, and hormonal therapy, often face significant challenges, including systemic toxicity and reduced efficacy, particularly in the advanced stages of the disease. The treatment of cervical cancer is further complicated by tumor heterogeneity, resistance mechanisms to chemotherapeutic drugs, and the persistent presence of HPV. However, in recent years, nanotechnological interventions, particularly solid lipid nanoparticles (SLNs), have gained increasing attention owing to their robust potential to effectively deliver chemotherapeutic agents while minimizing systemic toxicity. SLNs present a compelling solution for reducing side effects, enhancing drug solubility, improving stability and bioavailability, and overcoming the limitations and resistance associated with conventional treatment strategies.

Methods: To provide the context and evidence, relevant publications were searched on Google Scholar, PubMed, ScienceDirect, Dimensions AI, and EBSCO host, using specific keywords such as “cervical cancer”, “drug loading”, “encapsulation efficiency”, “HPV”, “sustained drug release”, and “solid lipid nanoparticles (SLNs)”. We did not impose any restrictions on the publication date during the selection of papers. However, it is imperative to highlight that the initial reports containing specified keywords began publication in 2013.

Conclusion: SLNs represent a promising frontier in drug delivery, particularly within cervical cancer therapeutics, because of their ability to facilitate the targeted delivery of chemotherapeutic agents and genetic materials. The potential of SLNs to encapsulate and protect vital therapeutic compounds presents significant opportunities for developing innovative treatment strategies including DNA and peptide vaccines. However, the lack of approved SLN-encapsulated vaccines for cervical cancer underscores the need for rigorous in vivo research and clinical trials to validate their safety and efficacy. Future studies should not only optimize SLNs for various agents but also explore diverse combination therapies to enhance therapeutic outcomes.

Introduction

Cervical cancer (CC) develops from a malignant epithelial tumor that leads to the proliferation of cells in the cervix. The predominant cause is persistent infection of Human papillomavirus (HPV), particularly HPV 16 and 18.1 Moreover, HIV-infected females have a 6-fold increased risk of developing CC compared to the general population.2 Emerging evidence suggests that HIV and HPV co-infection significantly contributes to cervical carcinogenesis through multifactorial viral interactions, encompassing immunosuppression, chronic inflammation, and the induction of epithelial–mesenchymal transition (EMT)3 (Table 1). The disease commonly presents as either less common adenocarcinoma (20–30%) or more common squamous cell carcinoma (70–80%).4,5 Additionally, factors such as multiple sexual partners,6,7 consistent use of oral contraceptives,6 early initiation of sexual activity,7 and a higher number of vaginal deliveries8,9 are also associated with the development of CC. The risk factors associated with the development of cervical cancer are illustrated in Fig. 1.10 Prognostic factors, including depth of cervical stromal invasion, tumor size, lymph node involvement, histological features, and International Federation of Gynecology and Obstetrics (FIGO) cancer stage, influence the prognosis of CC.11–13 Higher FIGO stage, increased node involvement, larger tumors, and deeper invasion are associated with poorer prognosis, leading to worsened overall survival (OS) and disease-free survival (DFS).

CC ranks as the third leading cause of death in women globally and is the second most frequently diagnosed cancer in women, especially those under 25 years of age.14 In 2020, there were 341 833 reported cases of CC worldwide, with a total of 604 127 new cases.15 According to Global Cancer Statistics, it is projected that there will be approximately 13 820 new cases and 4360 deaths in 2024 due to CC in the US.16 The incidence and mortality of CC vary based on the geographic and socioeconomic status of the country, with a heavy burden on low-middle-income countries (LMICs) and those with a lower Human Development Index (HDI).17 Astonishingly, 88% of all deaths and 83% of new CC cases occur in LMICs, including India, Sub-Saharan Africa, and Latin America.15,18

The treatment of CC depends on the stage and extent of spread. This includes surgery, radiotherapy, and chemotherapy, with increasing research on immunotherapy and targeted therapy.19 The National Comprehensive Cancer Network (NCCN) clinical practice guidelines recommend specific surgical procedures, such as conization, loop electrosurgical excision procedure (LEEP), or radical trachelectomy, for fertility preservation in women diagnosed with early stage disease.5 For women of childbearing age, radical hysterectomy or total hysterectomy with or without salpingo-oophorectomy is the treatment of choice.20,21 Radical hysterectomy using the open technique is the preferred option for tumors greater than 2 cm and larger cervical lesions.22 In the case of locally advanced stages (FIGO IIB/IIIB and FIGO IVA), concurrent chemotherapy with radiation therapy (RT) [external beam radiation therapy (EBRT), brachytherapy (internal RT), and intensity-modulated radiotherapy (IMRT)] followed by surgery is the most widely used method for managing CC.23,24 RT alone is not used for treatment due to its association with numerous adverse effects such as abdominal cramps, diarrhea, pelvic pain, skin toxicity, and lymphedema, which reduce the quality of life (QoL).25 Moreover, the treatment of locally advanced disease with chemoradiation has been associated with a high failure rate of 30–50%.26 In treating metastatic CC (Stage FIGO IVB) and locally advanced cervical cancer, pelvic exenteration for localized recurrence and chemotherapy alone, or in combination with radiation therapy, followed by surgery are crucial treatment options.27 Cisplatin is the most effective single agent, and the European Society for Medical Oncology (ESMO) recommends cisplatin over radiotherapy for local control and survival.28 Research has shown that the efficacy of cisplatin increases when it is combined with other chemotherapeutic agents.29,30 In a phase III study conducted by a gynecologic oncologic group, it was reported that combining cisplatin with topotecan and paclitaxel resulted in response rates of 39% and 29%, respectively.31 However, the median progression-free survival (mPFS) and median overall survival (mOS) for metastatic and recurrent CC remain low despite advances in treatment.28

The combination of targeted therapies, such as Bevacizumab with Cisplatin, has significantly improved progression-free survival (PFS) and overall survival (OS) in metastatic diseases.32,33 Additionally, immunotherapy targeting HPV oncogenes has been found to effectively target dysplastic precancerous lesions and malignant epithelial cervical cells.34 This exploration has led to the development of various checkpoint blockades, vaccines, and adoptive T-cell therapies, each with varying rates of success and many currently under clinical trials.35

Despite the wide range of treatment options, CC still faces numerous obstacles, particularly in the treatment of metastatic and locally advanced disease. There is a significant need to improve the survival outcomes of patients with stages IB3 to IVA undergoing chemoradiation.36 Moreover, the long-term side effects of these therapies are a major concern due to the potential risks of bladder, bowel, and sexual dysfunction, severely impacting prognosis.37 This highlights the urgent need for novel therapeutic approaches for the treatment of CC, particularly to achieve modest benefits for mOS and mPFS. Therefore, it is imperative to explore innovative delivery platforms, such as nanostructured lipid carriers (NLC), polymeric nanocarriers, and solid lipid nanoparticles (SLNs), which offer promising advantages in terms of drug bioavailability, tumor selectivity, and toxicity reduction.38–40 The following section discusses the evolution and potential of nanotechnology, especially SLNs, as a transformative approach in CC therapy. This transformative approach can provide personalized therapy, minimize adverse effects, and optimize treatment efficacy. Current research is primarily focused on utilizing nanotechnological tools to enhance drug delivery, reduce side effects, ensure accurate diagnosis, and improve overall survival in the management of CC.41,42 Extensive studies have been conducted on nanocarriers, such as lipid nanoparticles, dendrimers, and liposomes, because of their potential to cross the cell membrane and accumulate at the tumor site, thereby increasing the concentration of the drug at the target.43,44 Furthermore, these nanocarriers can also play a crucial role in developing cost-effective HPV vaccines to enhance vaccine efficacy for the successful prevention of CC in women at higher risk.45,46

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Table 2. Overview of SLN formulation and evaluation parameter

Excipients mentioned in the paper beside others: Gelucire® 50/13, Span® 85, Tween® 80, dichloromethane, DOTAP, dimethylsulfoxide, PEG 6000, Polysorbate 80, Glyceryl monostearate, lecithin soy

Pooja Tiwary, Krishil Oswal, Ryan Varghese, Ravi Vamsi Perib and Pardeep Gupta, Solid lipid nanoparticles in cervical cancer: a comprehensive review of a decade of progress and prospects, Article information, DOI https://doi.org/10.1039/D5PM00109A

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