The most common malignant tumor in women worldwide is breast cancer. In 2022, the occurrence and mortality of breast cancer in women were about 2.3 million and 0.68 million, respectively, and by 2040, the values will reach more than 3 million new cases and 1 million deaths per year [1]. Despite its greater occurrence rate in developed countries, the death rate is predominantly higher in developing and emerging countries [1]. Much research has been performed to achieve newer therapeutics, including receptor-specific drug carriers for treating breast adenocarcinoma [2].

Target-specific drug delivery for treating cancer patients follows either passive targeting therapy or an active targeted approach. Passive tumor drug targeting relies on enhanced permeation and retention (EPR) in the tumor micro-environments. Active targeting strategies rely on targeting receptor overexpression on the tumor cells [3]. Ormeloxifene (OLF) (also known as centchroman) is an oral non-steroidal contraceptive agent and a Selective Estrogen Receptor Modulator (SERM) developed by Central Drug Research Institute, Lucknow, India. OLF is lipophilic and has highly encouraging pharmacokinetic and pharmacodynamic characteristics. A selective estrogen receptor modulator, Ormeloxifene, acts as estrogenic in bones, and antiestrogenic in uterus and breasts [4]. The antiestrogenic action of OLF makes it an excellent choice for treating breast cancer [4]. Many preclinical and clinical studies indicated that OLF has intense therapeutic action in breast cancer and provides repurposing of its use in chemotherapy [5]. A previous clinical study found that 38.5% of patients with breast cancer treated with OLF demonstrated better anticancer efficacy in older postmenopausal women [5]. Formulating polymer-based nanoparticles (NP) for its delivery can improve the chemotherapeutic activity of OLF [6]. Nanoparticle delivery controls drug release, alters pharmacokinetic profiles, achieves targeted delivery, and minimizes systemic toxicity [6].

Although ormeloxifene is a selective estrogen receptor modulator (SERM), it has been reported to show anticancer potential against MDA-MB-231 triple-negative breast cancer cells (TNBC) [7,8]. While chemotherapy with anthracyclines and taxanes is currently used as a standard therapy for TNBC, there is a need for alternative therapies that may be more effective and/or have fewer side effects. Ormeloxifene has been shown to inhibit the growth of TNBC cells in vitro and in animal models and may be effective as a single agent or in combination with other treatments [9]. Murine xenotransplanted models, such as the MDA-MB-231 model, provide a platform for preclinical research. By studying the effects of ormeloxifene in these models, researchers can gain more insights into efficacy and its potential mechanisms of drug action.

Folate receptor-alpha is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein and has narrow expression in normal cells. Previous researchers have reported overexpression of folate receptor-alpha on carcinomas of the ovary, breast, and endometrium, and non-small cell lung adenocarcinoma [10]. Folate receptor-alpha has limited tissue distribution [10]. Its differential expression in certain malignancies makes the receptor an attractive target for targeted therapy [11]. Poly (lactic-co -glycolic) acid (PLGA) is a US-FDA (the United States Food and Drug Administration)-approved biodegradable polymer that can be administered in the intravenous dosage form. Extensive literature reviews and previous studies demonstrated the suitability of PLGA (50:50) for controlled drug release applications [12,13]. Initially, we conducted a specific preliminary study to select this polymer grade. The decision was based on primary data of different grades (50:50, 75:25, and 85:15) of the polymer used to develop the formulation. Finally, we chose this grade due to its higher drug (Ormeloxifene) loading, encapsulation efficiency, and % yield. Reports suggest that in-vivo drug release occurred for 5–6 weeks before getting the polymer completely biodegraded and reabsorbed [14,15].

Folic acid conjugated with a tripeptide (lysine-glycine-histidine) (FA-Pep) has good uptake and internalization in different folate-positive cell lines [16]. To increase OLF's anticancer activity, we designed and formulated FA-Pep-conjugated PLGA nanoparticles encapsulated with OLF as a targeted nanoformulation to improve its therapeutic action in breast cancer.