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

Abstract

It is almost four decades since N-(2-hydroxypropyl)methacrylamide (HPMA) – based copolymers arose as drug carriers. Although fundamentals have been established and significant advantages have been proved, the commercialization of this platform technology was hampered due to modest outcome of clinical trial initiated with PK1, the symbol of first generation polymer-drug conjugates. In this review, we illustrate the exciting progress and approaches offered by more effective 2nd generation HPMA-based polymer-drug conjugates in cancer treatment. For example, a new synthetic strategy endorses inert HPMA polymer with biodegradability, which permitted to prepare high molecular weight HPMA-drug conjugates with simple linear architecture while maintaining good biocompatibility. As expected, extended long-circulating pharmacokinetics and enhanced antitumor activities were achieved in several preclinical investigations. In addition, greater inhibition of tumor growth in combination regimes exhibits the remarkable capability and flexibility of HPMA-based macromolecular therapeutics. The review also discusses the main challenges and strategies for further translation development of 2nd generation HPMA-based polymer-drug conjugates.

Ribonuclease A modification with poly[N‐(2‐hydroxypropyl)methacrylamide] copolymers: new route of synthesis and purification

“…Depending on the final application, different PDI are acceptable. For drug delivery applications, it is crucial to obtain homogeneous conjugates due to dosage issues and reproducibility . However, some industrial applications like enzymatic catalysis do not require homogeneous polymer–enzymes conjugates.…”

“…Moreover, all HMPA–drugs conjugates remain either in clinical trials or discarded due to issues like wide molecular weight distribution and heterogenicity of the results. On the one hand, the advantages of HPMA encourages these drawback to be overcome . On the other hand, the conjugation of HPMA copolymers with therapeutic proteins remains poorly explored.…”

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

“…were discontinued in 2008 because of lack of efficacy [198]. Other polymeric systems also entered clinical trials ( Table 2).…”

Improved mitochondrial targeting effect of HPMA copolymer by SS20 peptide mediation and nonendocytosis pathway

“…Water soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer is considered to be an excellent drug delivery vehicle for its nonimmunogenicity, nontoxicity, biocompatibility, and multifunctionality. [22][23][24] Hence, in this study, SS20 peptide modified HPMA copolymers were developed to enhance mitochondria accumulation without being trapped in endosomes/lysosomes. Overall, physicochemical characteristics of HPMA copolymers were investigated in detail.…”

“…pharmacokinetics study, healthy male BALB/c mice(20-22 g) were randomly divided into two groups (n = 7) and intravenously injected with P-Cy5 and P-Cy5-SS20 (Cy5 equivalent concentration 2.5 mg/ kg). At predetermined time points(1,3,6,12,24, 48, 72, and 96 hours), blood samples (20 μL) were taken from the orbital, and the fluorescence intensity of each sample was measured with a Varioskan Flash (excitation at 642 nm and emission at 662 nm). The blood pharmacokinetic parameters were analyzed using a noncompartmental model with PK Solver software.…”