Clinical applications of many anti-cancer drugs are restricted due to their hydrophobic nature, requiring use of harmful organic solvents for administration, and poor selectivity and pharmacokinetics resulting in off-target toxicity and inefficient therapies. A wide variety of carrier-based nanoparticles have been developed to tackle these issues, but such strategies often fail to encapsulate drug efficiently and require significant amounts of inorganic and/or organic nanocarriers which may cause toxicity problems in the long term. Preparation of nanoformulations for the delivery of water insoluble drugs without using carriers is thus desired, 2 requiring elegantly designed strategies for products with high quality, stability and performance. These strategies include simple self-assembly or involving chemical modifications via coupling drugs together or conjugating them with various functional molecules such as lipids, carbohydrates and photosensitizers. During nanodrugs synthesis, insertion of redox-responsive linkers and tumor targeting ligands endows them with additional characteristics like on-target delivery, and conjugation with immunotherapeutic reagents enhances immune response alongside therapeutic efficacy. This review aims to summarize the methods of making carrier-free nanodrugs from hydrophobic drug molecules, evaluating their performance, and discussing the advantages, challenges, and future development of these strategies.
Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.
Lonidamine (LND) can act on mitochondria and inhibit energy metabolism in cancer cells and therefore has been used together with chemotherapy drugs for synergistically enhanced therapeutic efficacy. However, its use is hindered by the poor solubility and slow diffusion in the cytoplasm. To address these problems, we designed and prepared aqueous dispersible nanoparticles (NPs) containing integrated components including triphenylphosphine (TPP) to target the mitochondria of cells and LND and doxorubicin (DOX) for synergistic cancer treatment and conquering drug resistance. This design allows the NPs to concentrate in the mitochondria of cells, solve the low solubility of LND, and contain very high load of LND and DOX in comparison with previously reported drug-delivery systems based on various carrier nanomaterials. Detailed mechanism studies reveal that TPP-LND-DOX NPs could induce significant reactive oxygen species production, mitochondrial membrane potential decrease, and mitochondrial apoptosis pathway, thereby leading to great cytotoxicity in cancer cells. In vivo anticancer activities indicate that TPP-LND-DOX NPs exhibit the highest efficacy in tumor inhibition among all tested groups and show high effectiveness in drug-resistant model. This work demonstrates the potential use of our TPP-LND-DOX NPs to jointly promote the mitochondria apoptosis pathway and contribute to conquer drug resistance in cancer therapy.
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