Cancer, with its diversity, heterogeneity, and complexity, is a significant contributor to global morbidity, disability, and mortality, highlighting the necessity for transformative treatment approaches. Photodynamic therapy (PDT) has aroused continuous interest as a viable alternative to conventional cancer treatments that encounter drug resistance. Nanotechnology has brought new advances in medicine and has shown great potential in drug delivery and cancer treatment. For precise and efficient therapeutic utilization of such a tumor therapeutic approach with high spatiotemporal selectivity and minimal invasiveness, the carrier-free noncovalent nanoparticles (NPs) based on chemo-photodynamic combination therapy is essential. Utilizing natural products as the foundation for nanodrug development offers unparalleled advantages, including exceptional pharmacological activity, easy functionalization/modification, and well biocompatibility. The natural-product-based, carrier-free, noncovalent NPs revealed excellent synergistic anticancer activity in comparison with free photosensitizers and free bioactive natural products, representing an alternative and favorable combination therapeutic avenue to improve therapeutic efficacy. Herein, a comprehensive summary of current strategies and representative application examples of carrier-free noncovalent NPs in the past decade based on natural products (such as paclitaxel, 10-hydroxycamptothecin, doxorubicin, etoposide, combretastatin A4, epigallocatechin gallate, and curcumin) for tumor chemo-photodynamic combination therapy. We highlight the insightful design and synthesis of the smart carrier-free NPs that aim to enhance PDT efficacy. Meanwhile, we discuss the future challenges and potential opportunities associated with these NPs to provide new enlightenment, spur innovative ideas, and facilitate PDT-mediated clinical transformation. 

Natural-product-based, Carrier-free, Noncovalent Nanoparticles for Tumor Chemo-photodynamic Combination Therapy.

High solubility in water and physiological fluids is an indispensable requirement for the pharmacological efficacy of an active pharmaceutical ingredient. Indeed, it is well established that pharmaceutical substances exhibiting limited solubility in water are inclined towards diminished and inconsistent absorption following oral administration, consequently resulting in variability in therapeutic outcomes. The current advancements in combinatorial chemistry and pharmaceutical design have facilitated the creation of drug candidates characterized by increased lipophilicity, elevated molecular size, and reduced aqueous solubility. Undoubtedly, the issue of poorly water-soluble medications has been progressively escalating over recent years. Indeed, 40% of the top 200 oral medications marketed in the United States, 33% of drugs listed in the US pharmacopoeia, 75% of compounds under development and 90% of new chemical entities are insufficiently water-soluble compounds. In order to address this obstacle, formulation scientists employ a variety of approaches, encompassing both physical and chemical methods such as prodrug synthesis, salt formation, solid dispersions formation, hydrotropic substances utilization, solubilizing agents incorporation, cosolvent addition, polymorphism exploration, cocrystal creation, cyclodextrins complexation, lipid formulations, particle size reduction and nanoformulation techniques. Despite the utilization of these diverse approaches, the primary reason for the failure in new drug development persists as the poor aqueous solubility of pharmaceutical compounds. This paper, therefore, delves into the foundational principles that underpin the implementation of various formulation strategies, along with a discussion on the respective advantages and drawbacks associated with each approach. Additionally, a discourse is provided regarding methodological frameworks for making informed decisions on selecting an appropriate formulation strategy to effectively tackle the key challenges posed during the development of a poorly water-soluble drug candidate. 

Pharmaceutical approaches for enhancing solubility and oral bioavailability of poorly soluble drugs

Growing evidence demonstrates that reactive oxygen species (ROS) is closely related to many chronic disease progressions, such as atherosclerosis and rheumatoid arthritis because the over-expressed ROS caused long-term oxidative stress in the body easily evolve into the chronic injury of tissue. Therefore, the development of ROS scavengers to prevent and treat ROS-related chronic diseases is significant. Among the numerous developed or discovered ROS scavengers, natural dietary ROS scavengers that existed in food such as curcumin and vitamin C, received great attention because they are naturally occurring and many of them have been used in medicine and health care products. However, some of them suffer from inherent defects like instability or too fast metabolism in vivo. These defects greatly limit their bioavailability and practical applications. Recently, it is found that the nanolization of dietary ROS scavengers can effectively improve their bioavailability and thus ameliorate therapeutic effects of ROS-related chronic diseases. Nevertheless, the systematic summarization of dietary ROS scavenger-based nanomaterials against ROS-related chronic disease is still rare. Herein, we attempt to give a review to inspire the research enthusiasm. In this review, firstly, the common types of dietary ROS scavengers in daily life, their main dietary sources, bioactivities as well as chronic disease applications and representative ROS-scavenging mechanism are covered. Secondly, the general strategies to improve bioavailability of dietary ROS scavengers based on the nanolization are discussed. Thirdly, the applications and optimized design of dietary ROS scavenger-based nanomaterials against ROS-related various chronic diseases are systematically summarized. Finally, the challenges and future outlooks of this field are pointed out. 

Natural dietary ROS scavenger-based nanomaterials for ROS-related chronic disease prevention and treatment

Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide. Conventional treatments for HCC include drugs, radiation, and surgery. Despite the unremitting efforts of researchers, the curative effect of HCC has been greatly improved, but because HCC is often found in the middle and late stages, the curative effect is still not satisfactory, and the 5-year survival rate is still low. Nanomedicine is a potential subject, which has been applied to the treatment of HCC and has achieved promising results. Here, we summarized the factors affecting the efficacy of drugs in HCC treatment and the strategies for improving the efficacy of nanotechnology-based drugs in HCC, reviewed the recent applications’ progress on nanotechnology-based drugs in HCC treatment, and discussed the future perspectives and challenges of nanotechnology-based drugs in HCC treatment.

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment

Altrenogest (ALT), a synthetic progestogen, serves a critical role in estrus synchronization among animals like gilts and mares. However, its practical application in animal husbandry is hampered due to its poor solubility and limited oral bioavailability. To address this challenge, a solvent evaporation method was employed to create an inclusion complex of ALT with hydroxypropyl-β-cyclodextrin (ALT/HP-β-CD). The formation of this inclusion complex was confirmed by scanning electron microscopy, power X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, and docking calculations. In addition, we further conducted pharmacokinetic investigation involving gilts, comparing ALT/HP-β-CD inclusion complex to an ALT oral solution. The physicochemical characterization results unveiled a transformation of ALT's crystal morphology into an amorphous state, with ALT effectively entering the cavity of HP-β-CD. Compared with ALT, the solubility of ALT/HP-β-CD inclusion complex increased by 1026.51-fold, and its dissolution rate demonstrated significant improvement. Pharmacokinetic assessments further revealed that the oral bioavailability of ALT/HP-β-CD inclusion complex surpassed that of the ALT oral solution, with a relative bioavailability of 114.08 %. In conclusion, complexation with HP-β-CD represents a highly effective approach to improve both the solubility and oral bioavailability of ALT. 

Enhancement of the solubility and oral bioavailability of altrenogest through complexation with hydroxypropyl-β-cyclodextrin.

Prodrug strategy is critical for innovative drug development. Structural modification is the most straightforward and effective method to develop prodrugs. Improving drug defects and optimizing the physical and chemical properties of a drug, such as lipophilicity and water solubility, changing the way of administration can be achieved through specific structural modification. Designing prodrugs by linking microenvironment-responsive groups to the prototype drugs is of great help in enhancing drug targeting. In the meantime, making connections between prodrugs and suitable drug delivery systems could realize drug loading increases, greater stability, bioavailability and drug release control. In this paper, lipidic, water-soluble, pH-responsive, redox-sensitive and enzyme-activatable prodrugs are reviewed on the basis of structural modification.

Structure modification: a successful tool for prodrug design.

Lipid-based formulations: A promising approach for poorly soluble drug delivery via the intestinal lymphatic system

Advances in Sources, Content Determination, and Bioactivity of 20α-Hydroxyprogesterone.

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Structure modification: a successful tool for prodrug design.

Lipid-based formulations: A promising approach for poorly soluble drug delivery via the intestinal lymphatic system

Advances in Sources, Content Determination, and Bioactivity of 20α-Hydroxyprogesterone.