Researchers at Osaka Metropolitan University have developed a new drug delivery approach that increases the solubility of the anticancer drug paclitaxel. Modern developments in pharmacy have led to the discovery of many molecules with strong therapeutic potential. However, many of these candidates exhibit unfavorable physicochemical properties that hinder their effective application.
That is why scientists are increasingly developing advanced drug delivery systems (DDS) that enable drug dissolution, more efficient transport through the body, and targeted action on tumor tissue. The latest research indicates that newer strategies can significantly improve the effectiveness of certain anticancer therapies, while simultaneously reducing side effects.
Challenges With Modern Drug Compounds
Many modern drugs in development exhibit poor water solubility and a relatively high molecular weight. These properties often limit bioavailability, making it difficult to achieve a sufficient drug concentration in the body.
In addition, certain drugs do not have a sufficiently selective distribution, so instead of concentrating in tumor tissue, they spread to healthy tissues. Such a distribution can cause pronounced side effects and also reduce overall therapeutic effectiveness.
Due to these problems, modern research focuses on developing DDS systems that enable the dissolution of poorly soluble molecules and their more precise delivery to targeted pathological tissues.
Targeting Paclitaxel Delivery
A research team from Osaka Metropolitan University focused on developing a system to improve the delivery of paclitaxel, a commonly used anticancer drug. This drug is used in the therapy of various malignancies, but its clinical application is hampered by its extremely low water solubility and high molecular weight of 854.
To overcome these difficulties, scientists investigated the potential of lipocalin-type prostaglandin D synthase (L-PGDS) as a paclitaxel carrer. The results of computer docking simulations, together with experimental solubility tests, showed that paclitaxel binds to L-PGDS primarily through hydrophobic interactions within the upper part of the β-barrel structure of this protein. Such an interaction led to a dramatic increase in drug solubility.
According to the research results, the solubility of paclitaxel increased approximately 3,600-fold compared to its behavior in phosphate-buffered saline, indicating the great potential of this approach to improve the delivery of anticancer drugs.
Adding a Cancer-Targeting Mechanism
To increase selectivity towards tumor cells, the researchers functionalized the L-PGDS protein by attaching the target peptide CRGDK to its C-terminal end, thereby constructing a modified complex designated L-PGDS-CRGDK.
The CRGDK peptide shows high affinity for neuropilin-1, which is overexpressed on the surface of malignant cells. By introducing this targeting motif, the carrier is optimized to recognize and bind to tumor cells, enabling more precise and efficient targeting of the site of action while reducing systemic distribution.
Promising Results in Laboratory Models
The system’s efficiency was evaluated in an in vivo model using mice implanted with MDA-MB-231 breast cancer cells, which represent a standard model for aggressive tumor research. The commercial formulation of paclitaxel demonstrated the expected antitumor activity during therapy, but its effect was transient and attenuated after discontinuation.
In contrast, the formulations based on the L-PGDS carrier (PTX/L-PGDS and PTX/L-PGDS-CRGDK) showed prolonged antitumor activity that persisted even after treatment ended. The variant PTX/L-PGDS-CRGDK, which demonstrated the most pronounced inhibition of tumor growth, stood out in particular, indicating an additional benefit of a targeted approach.
Potential Impact on Future Cancer Therapies
The results suggest that L-PGDS can serve as a biological carrier for the transport of molecules of higher molecular weight and limited solubility, and that the introduction of target peptides further improves specificity and therapeutic precision.
According to Professor Takashi Inui from Osaka Metropolitan University, the research confirmed the ability of the L-PGDS protein to stably bind relatively large molecules (up to approximately 850 Da), as well as that the modification of the carrier with a target peptide enables the selective delivery of drugs directly to malignant cells.
This approach represents a promising DDS strategy to overcome the limitations of poorly soluble anticancer drugs. In the long term, this system could serve as a basis for developing new therapeutic platforms that offer greater efficacy, improved bioavailability, and reduced risk of side effects.
