Investigation of the Therapeutic Potential of a Synergistic Delivery System through Dual Controlled Release of Camptothecin–Doxorubicin

Abstract

An ideal nanotherapeutic should enhance therapeutic efficacy of the drug while reducing side effects. This work reports development of a nanotherapeutic utilizing hyperbranched polymers as a platform for conjugating doxorubicin (DOX) and camptothecin (CPT) as potential synergistic therapies. The carrier also includes cyanine‐5 (Cy5) as an imaging tracer to monitor distribution and efficacy of the therapeutic, and a bispecific antibody (BsAb) as a cell targeting agent to increase accumulation and specificity for tumor tissue. The synergism of this drug combination is investigated by utilizing both redox‐ and hydrolytic release mechanisms of CPT and DOX, respectively. Drug release and cellular uptake studies confirm the proposed delivery mechanisms and subsequent intracellular trafficking of the drugs. In this particular case, a superadditive effect is observed in vitro for the two drugs when delivered by nanocarrier. This is enhanced when the carrier is targeted to epidermal growth factor receptor (EGFR) that is upregulated in the tumors. Moreover, tumor regression studies show that the synergistic therapeutic effect of combination nanocarriers has greater inhibition of xenograft tumor growth compared to treatments that deliver DOX or CPT alone, suggesting that codelivery of dual therapeutics using modular hyperbranched polymer carriers offers unique potential to regulate tumor growth.

M1 Macrophage-Derived Exosomes Loaded with Gemcitabine and Deferasirox against Chemoresistant Pancreatic Cancer

“…PANC-1/GEM tumor spheroids were formed in microwell devices using our reported method [ 31 , 32 , 33 ]. The culture medium was changed every 2 days and the formation of the tumor spheroids was monitored using a light microscope (OLYMPUS, CKX53,Tokyo, Japan).…”

Next‐Generation Polymeric Nanomedicines for Oncology: Perspectives and Future Directions

“…[57,58] In a simple incubation step, such bispecific antibodies are then able to decorate the surface of nanomedicines to produce a targeted construct without the need for complex synthetic chemistry approaches (Figure 3). [4] PEG-based polymeric nanomedicines remain ubiquitous in the field; nonetheless, ongoing work is now examining a range of alternative biocompatible polymers for the synthesis of novel materials. To achieve utility, these materials must satisfy several selection criteria such as solubility, biocompatibility, and low immunogenicity with ease of synthesis and functionalizable side chains being highly desirable to address Figure 4.…”

“…[ 57,58 ] In a simple incubation step, such bispecific antibodies are then able to decorate the surface of nanomedicines to produce a targeted construct without the need for complex synthetic chemistry approaches (Figure 3). [ 4 ]…”

“…[2,3] Nanomedicine Figure 1. Application and benefits of polymers in nanomedicine as polymeric linear/branched, [4,5] micellar, [6,7] or aggregate [8,9] nanoparticle formats, or as hybrids with biologics, typically as pharmacokinetic modifiers, [10,11] and as biocompatibilizer and stabilizer of nanocarrier templates. [12][13][14]…”

Effect of Chain‐End Chemistries on the Efficiency of Coupling Antibodies to Polymers Using Unnatural Amino Acids

“…[ 11,12 ] This can be addressed in some cases by using high‐affinity interactions between the antibody and synthetic material through the use of bispecific antibodies, but this is limited to select polymers with potential stability issues in vivo. [ 13,14 ]…”