Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non‐optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor‐targeting aptamers for effective low‐dose treatment. A nucleolin‐recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC50(31.9 n
Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non‐optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor‐targeting aptamers for effective low‐dose treatment. A nucleolin‐recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC50(31.9 n
- PAR ID:
- 10082035
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Angewandte Chemie International Edition
- Volume:
- 58
- Issue:
- 5
- ISSN:
- 1433-7851
- Page Range / eLocation ID:
- p. 1437-1441
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
Abstract m ) against MDA‐MB‐231 breast cancer cells in vitro, and exhibited in vivo efficacy at micro‐dose injections (500 and 350 μg kg−1 dose−1of DOX and CPT, respectively) that are 20–30‐fold lower than their previously‐reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology. -
Abstract Effective chemotherapy delivery for glioblastoma multiforme (GBM) is limited by drug transport across the blood–brain barrier and poor efficacy of single agents. Polymer–drug conjugates can be used to deliver drug combinations with a ratiometric dosing. However, the behaviors and effectiveness of this system have never been well investigated in GBM models. Here, we report flexible conjugates of hyaluronic acid (HA) with camptothecin (CPT) and doxorubicin (DOX) delivered into the brain using focused ultrasound (FUS). In vitro toxicity assays reveal that DOX‐CPT exhibited synergistic action against GBM in a ratio‐dependent manner when delivered as HA conjugates. FUS is employed to improve penetration of DOX‐HA‐CPT conjugates into the brain in vivo in a murine GBM model. Small‐angle x‐ray scattering characterizations of the conjugates show that the DOX:CPT ratio affects the polymer chain flexibility. Conjugates with the highest flexibility yield the highest efficacy in treating mouse GBM in vivo. Our results demonstrate the association of FUS‐enhanced delivery of combination chemotherapy and the drug‐ratio‐dependent flexibility of the HA conjugates. Drug ratio in the polymer nanocomplex may thus be employed as a key factor to modulate FUS drug delivery efficiency via controlling the polymer flexibility. Our characterizations also highlight the significance of understanding the flexibility of drug carriers in ultrasound‐mediated drug delivery systems.
-
Abstract FePO4NPs are of special interest in food fortification and biomedical imaging because of their biocompatibility, high bioavailability, magnetic property, and superior sensory performance that do not cause adverse organoleptic effects. These characteristics are desirable in drug delivery as well. Here, we explored the FePO4nanoparticles as a delivery vehicle for the anticancer drug, doxorubicin, with an optimum drug loading of 26.81% ± 1.0%. This loading further enforces the formation of Fe3+doxorubicin complex resulting in the formation of FePO4-DOX nanoparticles. FePO4-DOX nanoparticles showed a good size homogeneity and concentration-dependent biocompatibility, with over 70% biocompatibility up to 80 µg/mL concentration. Importantly, cytotoxicity analysis showed that Fe3+complexation with DOX in FePO4-DOX NPs enhanced the cytotoxicity by around 10 times than free DOX and improved the selectivity toward cancer cells. Furthermore, FePO4NPs temperature-stabilize RNA and support mRNA translation activity showing promises for RNA stabilizing agents. The results show the biocompatibility of iron-based inorganic nanoparticles, their drug and RNA loading, stabilization, and delivery activity with potential ramifications for food fortification and drug/RNA delivery.
-
Abstract Small‐molecule drugs are used extensively in clinics for cancer treatment; however, many antitumor chemical drugs dissolve poorly in aqueous solution. Their poor solubility and nonselective delivery in vivo often cause severe side effects. Here, the application of RNA nanotechnology to enhance the solubility of hydrophobic drugs, using camptothecin (CPT) for proof‐of‐concept in targeted delivery for cancer treatment is reported. Multiple CPT prodrug molecules are conjugated to RNA oligos via a click reaction, and the resulting CPT‐RNA conjugates efficiently self‐assemble into thermodynamically stable RNA three‐way junction (3WJ) nanoparticles. The RNA 3WJ is covalently linked with seven hydrophobic CPT prodrug molecules through cleavable ester bonds and a folic acid ligand for specific tumor targeting while remaining soluble in aqueous solutions without detectable aggregation at therapeutic dose. This CPT‐RNA nanoparticle exhibits efficient and specific cell binding and internalization, leading to cell apoptosis. Tumor growth is effectively inhibited by CPT‐RNA nanoparticles; the targeted delivery, strengthened by tumor ligand, further enhances tumor suppression. Compared with the traditional formulation, solubilization of CPT in aqueous buffer using RNA nanoparticles as a carrier is found to be safe and efficacious, demonstrating that RNA nanoparticles are a promising platform for the solubilization and the delivery of hydrophobic antitumor drugs.
-
Abstract It is considered a significant challenge to construct nanocarriers that have high drug loading capacity and can overcome physiological barriers to deliver efficacious amounts of drugs to solid tumors. Here, the development of a safe, biconcave carbon nanodisk to address this challenge for treating breast cancer is reported. The nanodisk demonstrates fluorescent imaging capability, an exceedingly high loading capacity (947.8 mg g−1, 94.78 wt%) for doxorubicin (DOX), and pH‐responsive drug release. It exhibits a higher uptake rate by tumor cells and greater accumulation in tumors in a mouse model than its carbon nanosphere counterpart. In addition, the nanodisk absorbs and transforms near‐infrared (NIR) light to heat, which enables simultaneous NIR‐responsive drug release for chemotherapy and generation of thermal energy for tumor cell destruction. Notably, this NIR‐activated dual therapy demonstrates a near complete suppression of tumor growth in a mouse model of triple‐negative breast cancer when DOX‐loaded nanodisks are administered systemically.