Clinical developments of antitumor polymer therapeutics

Abstract

Polymer therapeutics encompasses polymer-drug conjugates that are nano-sized, multicomponent constructs already in the clinic as antitumor compounds, either as single agents or in combination with other organic drug scaffolds. Nanoparticle-based polymer-conjugated therapeutics are poised to become a leading delivery strategy for cancer treatments as they exhibit prolonged half-life, higher stability and selectivity, water solubility, longer clearance time, lower immunogenicity and antigenicity and often also specific targeting to tissues or cells. Compared to free drugs, polymer-tethered drugs preferentially accumulate in the tumor sites unlike conventional chemotherapy which does not discriminate between the cancer cells and healthy cells, thereby causing severe side-effects. It is also desirable that the drug reaches its site of action at a particular concentration and the therapeutic dose remains constant over a sufficiently long period of time. This can be achieved by opting for new formulations possessing polymeric systems of drug carriers. However, many challenges still remain unanswered in polymeric drug conjugates which need to be readdressed and therefore, can broaden the scope of this field. This review highlights some of the antitumor polymer therapeutics including polymer-drug conjugates, polymeric micelles, polymeric liposomes and other polymeric nanoparticles that are currently under investigation.

Fig. 1. Schematic representation of the EPR effect. Reprinted with permission from ref. 42, Royal Society of Chemistry.

Fig. 2. Ringsdorf's model of polymer–drug conjugate.

Fig. 3. Structures of PEG–drug conjugates in clinical trials.

Fig. 4. Structures of HPMA copolymer doxorubicin (PK1) and HPMA copolymer-doxorubicin galactosamine (PK2).

Fig. 5. Structures of (a) PNU166945 and (b) AP 5346.

Fig. 6. Structures of other polymer–drug conjugates.

Fig. 7. Schematic representation of a block copolymer micelle; lipophilic drug (red color) is encapsulated in the micelle core. Reprinted with permission from ref. 98, Elsevier.

Fig. 8. Serial CT scans of a 60 year-old male with pancreatic tumor who was treated with NK105 at a dose level of 150 mg m⁻². Baseline scan (upper panels) showing multiple metastasis in the liver. Partial response, characterized by a more than 90% decrease in the size of the liver metastasis (lower panels) compared with the baseline scan. The antitumor response was maintained for nearly 1 year. Reprinted with permission from ref. 113, Springer.

Fig. 9. Structure of liposome. Reprinted with permission from ref. 11, Elsevier.

Fig. 10. A polymeric nanoparticle.

Fig. 11. Schematic diagram representing the mode of action of targeted multifunctional nanoparticle (NP). Reprinted with permission from ref. 170.

Fig. 12. Structures of biodegradable polymers for encapsulation of antitumor drugs.

Fig. 13. Self-assembly of (A) RGD4C-PEO-b-P(CL-Hyd-DOX) and (B) RGD4C-PEO-b-P(CL-Ami-DOX) copolymers into targeted micelles. Reprinted with permission from ref. 184, Elsevier.

Fig. 14. Schematic illustration of H₂O₂-responsive PLGA nanoparticles containing Pt(ii) drugs and O₂-generating catalase and the mechanism of drug release by H₂O₂. Reprinted with permission from ref. 185, Royal Society of Chemistry.

Scheme 1. Schematic illustration of the synthesis of polymer drug conjugates of PEG-b-P(HEMA-PTX) via an disulfide linker and its drug release mechanism. Reprinted with permission from ref. 186, Royal Society of Chemistry.

Fig. 15. Chemical structure of HA-DOX and PEEP. Reprinted with permission from ref. 189, American Chemical Society.

Fig. 16. Structure of Ac-Phe-Lys-PABC-ADM hydrochloride. Reprinted with permission from ref. 191, John Wiley & Sons.

Shazia Parveen

Farukh Arjmand

Sartaj Tabassum