Fabrication of lipid-modified drug nanocrystals loaded injectable hydrogel for breast cancer therapy

Abstract

The current study includes the design of soluplus stabilized, lipid-coated, and fucoidan-oleylamine conjugate modified paclitaxel nanocrystals. The nanocrystals (Lipid-NCs) were about 100 nm, homogeneous, stable and showed improved drug release compared to pure PTX. The nanocrystals were subsequently loaded in an in situ gel-forming hydrogel for the intratumoral injection. The resulting hydrogel exhibited a sol-form at the lower temperature of 2–8 °C while converted to a gel-form at the body temperature. The injectable hydrogel had a reasonable viscosity, an acceptable pH, good syringeability, and a quick sol–gel transition. The hydrogel demonstrated high payload potential, homogeneous distribution, and controlled long-term drug release. In vivo studies revealed the higher efficacy of Lipid-NCs hydrogel in tumor inhibition while avoiding systemic toxicity, compared to pure PTX-loaded hydrogel and intravenously administered PTX. In conclusion, nanocrystal-loaded hydrogel is a promising localized drug delivery system for breast cancer therapy.

Introduction

Breast cancer is one of the most common and aggressive types of cancer worldwide, with a high fatality rate [1]. Surgical resection of local breast tumor is the preferred treatment but has a high risk of incomplete tumor removal and surgical complications [2]. These can lead to induction of several pathophysiological processes that trigger the tumor recurrence, resulting in surgery induced-metastasis [3, 4]. The conventional treatment includes the intravenous administration of anticancer drugs; however they are associated with drug distribution to major organs of body, systemic toxicity, limited drug availability at tumor site, poor therapeutic effects, occurrence of drug resistance and advancement of cancer to metastases [5,6,7]. Therefore, strategies for maximizing the drug availability at tumor site are required to prevent postoperative cancer recurrence. In this regard, localized drug delivery systems have been observed more effective by maintaining drug concentration at target site for a prolonged period, minimizing organ distribution and thus diminishing systemic side effects [8, 9]. Recently, injectable hydrogels have been reported by many research scientists for the localized drug delivery and cancer therapy [10,11,12]. Injectable hydrogels exhibiting sol–gel transition at body temperature has been reported for various anticancer drug delivery applications. These consists of polymers that remain in sol-form suitable for injection and converts to gel-form at a physiological body temperature. The thermo-reversibility of hydrogel offers the advantages of easy administration via injection, gel-depot formation at tumoral tissues and extended residence at target site for continuous drug release [13].

Considering all the above facts, the objective of present work was formulation of paclitaxel loaded thermosensitive hydrogel for localized drug delivery and breast cancer therapy. Such hydrogel acts an effective drug carrier for intratumoral injection to form depot and provide controlled release at tumor region. However, PTX belonging to Biopharmaceutics Classification System (BCS) class IV exhibits low solubility and poor penetration, thereby hampering the drug release [14]. To improve the drug efficacy, PTX can be fabricated as nanocrystals. Nanocrystals owing to their size and surface properties withhold higher aqueous solubility and greater tumor tissues penetration. Additionally, lipid-coated nanocrystals (Lipid-NCs) can be prepared, further facilitating the fusion of lipid-particles with cancer cell membranes and hence promoting the intracellular drug delivery via phospholipid bilayer diffusion [15]. Lipid-NCs can control the drug release responsible for retaining maximum drug at site and can be equipped with molecules having selectivity towards cancer cells. Therefore, present work involved fabrication of PTX as drug nanocrystals using soluplus as stabilizer, soya-lecithin (SLec), cholesterol (Chol) & tocopherol polyethylene glycol succinate (TPGS) as lipid-membrane materials, and amphiphilic fucoidan-olylamine (FP-OA) conjugate as targeting moiety. Fucoidan are sulphated polysaccharides with high affinity towards cell surface receptors overexpressed on tumor cells [16]. Then, drug and nanocrystals were loaded in thermosensitive injectable hydrogel constructed with chitosan and pluronic F127 to give PTX-Gel, SPNC-Gel, and Lipid-NCs-Gel. The purpose was to investigate the effect of drug nanocrystals in improving therapeutic efficacy of drug towards management of breast cancer. Prepared nanocrystals and nanocrystals loaded hydrogels were evaluated for physicochemical, in vitro and in vivo anti-tumor characteristics.

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Materials

Fucoidan (Undaria pinnatifida) of medicine grade (98% fucoidan) was received as a gift sample from Nutra Green Biotechnology, Co., Ltd. Shanghai Lvshang Biotechnology, Shanghai-200129, China. Oleylamine, N-Ethyl-N’-(3-dimethylaminopropyl) carbodiimide (EDC), and N-Hydroxysuccinimide (NHS) were procured from SRL Pvt. Ltd. Paclitaxel (USP, 98–100%) was gifted by MSN Laboratories Pvt. Ltd., Unit II, Sy No: 50, Kardanur, Medak (Dist.), Telangana, India. Vitamin E TPGS NF Grade was procured from Antares Health Products, St. Charles, USA. A gift sample of soybean lecithin (SLec) was obtained from Lipoid, GmBH. Cholesterol extrapure AR, 99% (Chol), medical grade chitosan (Mwt, 100–300 kDa and 95% acetylation degree), and Pluronic F127 (Mwt 12,000 Da) were purchased from SRL chemicals, India. All the solvents used in the experiments were of HPLC grade.

Kumar, M., Jha, A., Goswami, P. et al. Fabrication of lipid-modified drug nanocrystals loaded injectable hydrogel for breast cancer therapy. Discover Nano 20, 30 (2025). https://doi.org/10.1186/s11671-025-04195-w