Low-Molecular-Weight Polymer–Drug Conjugates for Synergistic Anticancer Activity of Camptothecin and Doxorubicin Combinations

Abstract

Background: High-molecular-weight (MW) polymers (>50,000 Da) can be conjugated to chemotherapy drugs in order to improve their tumor accumulation, while low MW polymers ≤10,000 Da are often overlooked due to faster plasma clearance. Small polymers, however, may facilitate deeper tumor penetration. Materials & methods:Here, we investigate the anticancer efficacy of 10 kDa hyaluronic acid or poly(vinyl alcohol) conjugated to synergistic combinations of camptothecin and doxorubicin, with emphasis on chemical linker impacts. Results: Our results emphasize drug hydrolyzability for synergy preservation, and also demonstrate superior cancer cell inhibition with low MW polymer-drug conjugates. Conclusion: This study shows the high therapeutic potential of low MW polymer-drug conjugates for polychemotherapy delivery, and provides further insight into the development of polymer-drug therapeutics.

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

“…Higher molecular weight conjugates possess a longer intravascular half-life resulting in efficient extravasation into solid tumors; lower molecular weight conjugates may diffuse better into the solid tumor interior. While low molecular weight conjugates show high efficiency in animal models [73] they have difficulties in clinical settings [10] due to a short intravascular half-life. In a human body where the ratio of tumor to whole body is considerably smaller than in animals a sustained concentration gradient between vasculature and tumor is needed to achieve tumor accumulation.…”

A bone-resorption surface-targeting nanoparticle to deliver anti-miR214 for osteoporosis therapy

“…Previous clinical results have confirmed that PU has high drug-loading efficiency, excellent biocompatibility, low cytotoxicity, and good mechanical flexibility. 59,60 Serum-stability data suggested that PU protected miRNAs from degradation by endogenous enzymes, which confirmed it as a good carrier for small nucleic acid drugs. As such, Asp 8 -PU was developed as a bone-resorption-targeting system to deliver and release miRNAs.…”

Therapeutic polymeric nanomedicine: GSH-responsive release promotes drug release for cancer synergistic chemotherapy

“…Moreover, inefficient release of drugs from the nanomedicines aer internalization into cancer cells also signicantly reduce the synergistic effect. 27,28 The common attention is mainly paid to increasing corelease of multi-drugs in nanomedicine design, taking advantage of covalent linkage or physical interactions between chemotherapeutic drugs and functional materials. [29][30][31][32][33][34][35] Notably, glutathione (GSH)-responsiveness is an ideal candidate for the development of controlled drug release system because there is a signicant difference in GSH concentration between intracellular (2-10 mM) and extracellular environment (2-20 mM), so that the nanomedicine will be able to keep stable in extracellular environment and release the conjugated drug in the cells, thus enhancing the therapeutic efficacy while reducing the side effects.…”

“…The topoisomerase I inhibitor (CPT) and topoisomerase II inhibitor (DOX) with a complementary anticancer mechanism is used for combination therapy. [43][44][45][46][47][48][49] Beneting from the RAFT living polymerization, the polymerization degree of prodrug segment can be precisely controlled, so that the optimized ratio of two drugs can be easily modulated by changing the loading content. The synergistic chemotherapy of CPT and DOX is induced by the mPEG-b-PCPT/DOX nanomedicine through a "release promote release strategy", which is shown in Scheme 1.…”