Induction of Systemic Antitumour Resistance with Targeted Polymers (original) (raw)
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HPMA-based polymeric conjugates in anticancer therapeutics
Drug Discovery Today, 2020
Polymer therapeutics has gained prominence as an attractive structural polymer chemistry applicable in biomedicals. In this review, we discuss the development and capabilities of N-(2-hydroxypropyl) methacrylamide (HPMA) and HPMA-drug conjugates in cancer therapy. The design, architecture, and structural propert Q3 ies of HPMA make it a versatile system for the synthesis of polymeric conjugations for biomedical applications. Research suggests that HPMA could be a possible alternative for polymers such polyethylene glycol (PEG) in biomedical applications. Although numerous clinical trials of HPMA-drug conjugates are ongoing, no product has been successfully brought to market. Thus, further research is required to develop HPMA-drug conjugates as successful cancer therapeutics. Q5 ver, the effective targeting of drugs and macromolecules to pathogenic cells, specifically the intracellular compartment, remains a significant challenge, particularly against cancers. Research focuses on developing a selective/ targeted delivery vehicle for anticancer effectivity without harming heal Q6 thy cells. At the cellular level, the cell membrane and the inherent compartmentalization of organelles are additional obstacles [1]. To elicit effective therapeutic action, drugs, including macromolecules such as proteins, antibodies, small molecules, and antineoplastic agents, have to be delivered to their specific targets, mainly the cytoplasm or nucleus of cancer cells. However, many chemotherapeutics fail to target tumor cells because of their small size and/or molecular weight, low aqueous solubility, and poor pharmacokinetics (PK). In addition, following intravenous delivery, these agents are rapidly cleared from the circulation. Active and passive targeting are considered to be possible ways to ameliorate this problem to some extent. In active targeting, the polymer is directly conjugated with a ligand moiety, drug, or antibody, whereas in passive targeting, therapeutic carrier enters the tumor vasculature via the enhanced permeation and retention (EPR) effect [2-6]. Targeted delivery by increasing selectivity towards the target and decreasing toxicity can be achieved by carriers including liposomes (e.g., Doxil, Myocet, and Caelyx) [7,8], Reviews KEYNOTE REVIEW
Cancer Immunology, Immunotherapy, 2006
Linkage of doxorubicin (Dox) to a water-soluble synthetic N-(2-hydroxypropyl)methacrylamide copolymer (PHPMA) eliminates most of the systemic toxicity of the free drug. In EL-4 lymphoma-bearing C57BL/6 mice, a complete regression of pre-established tumours has been achieved upon treatment with Dox-PHPMA-HuIg conjugate. The treatment was effective using a range of regimens and dosages, ranging from 62.5 to 100% cured mice treated with a single dose of 10-20 mg of Dox eq./kg, respectively. Fractionated dosages producing lower levels of the conjugate for a prolonged time period had substantial curative capacity as well. The cured mice developed anti-tumour protection as they rejected subsequently re-transplanted original tumour. The proportion of tumour-protected mice inversely reflected the effectiveness of the primary treatment. The treatment protocol leading to 50% of cured mice produced only protected mice, while no mice treated with early treatment regimen (i.e. starting on day 1 after tumour transplantation) rejected the re-transplanted tumour. Exposure of the host to the cancer cells was a prerequisite for developing protection. The antitumour memory was long lasting and specific against the original tumour, as the cured mice did not reject another syngeneic tumour, melanoma B16-F10. The immunity was transferable to naı¨ve recipients in in vivo neutralization assay by spleen cells or CD8 + lymphocytes derived from cured animals. We propose an effective treatment strategy which eradicates tumours without harming the protective immune anti-cancer responses.
Clinical developments of antitumor polymer therapeutics
RSC Advances, 2019
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.
Polymer-drug conjugates: towards a novel approach for the treatment of endrocine-related cancer
Endocrine Related Cancer, 2005
The last decade has seen successful clinical application of polymer-protein conjugates (e.g. Oncaspar, Neulasta) and promising results in clinical trials with polymer-anticancer drug conjugates. This, together with the realisation that nanomedicines may play an important future role in cancer diagnosis and treatment, has increased interest in this emerging field. More than 10 anticancer conjugates have now entered clinical development. Phase I/II clinical trials involving N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1; FCE28068) showed a four-to fivefold reduction in anthracycline-related toxicity, and, despite cumulative doses up to 1680 mg/m 2 (doxorubicin equivalent), no cardiotoxicity was observed. Antitumour activity in chemotherapy-resistant/refractory patients (including breast cancer) was also seen at doxorubicin doses of 80-320 mg/m 2 , consistent with tumour targeting by the enhanced permeability (EPR) effect. Hints, preclinical and clinical, that polymer anthracycline conjugation can bypass multidrug resistance (MDR) reinforce our hope that polymer drugs will prove useful in improving treatment of endocrine-related cancers. These promising early clinical results open the possibility of using the water-soluble polymers as platforms for delivery of a cocktail of pendant drugs. In particular, we have recently described the first conjugates to combine endocrine therapy and chemotherapy. Their markedly enhanced in vitro activity encourages further development of such novel, polymer-based combination therapies. This review briefly describes the current status of polymer therapeutics as anticancer agents, and discusses the opportunities for design of second-generation, polymer-based combination therapy, including the cocktail of agents that will be needed to treat resistant metastatic cancer.
Enhanced cytotoxicity of a polymer–drug conjugate with triple payload of paclitaxel
Bioorganic & Medicinal Chemistry, 2009
The development of targeting approaches to selectively release chemotherapeutic drugs into malignant tissue is a major challenge in anticancer therapy. We have synthesized an N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymer-drug conjugate with an AB 3 self-immolative dendritic linker. HPMA copolymers are known to accumulate selectively in tumors. The water-soluble polymer-drug conjugate was designed to release a triple payload of the hydrophobic drug paclitaxel as a result of cleavage by the endogenous enzyme cathepsin B. The polymer-drug conjugate exhibited enhanced cytotoxicity on murine prostate adenocarcinoma (TRAMP C2) cells in comparison to a classic monomeric drug-polymer conjugate.
International journal of pharmaceutics, 2018
Utilizing the diverse features of biocompatible polymers to target drugs into the tumor/s has been a research hotspot since last decade. Such polymeric conjugates of anti-cancer drugs have proven their potential in providing sustained release of drugs with reduced systemic toxicity and improved tumor retention. Polymers like polyethylene glycol (PEG), N-(2-Hydroxypropyl) methacrylamide (HPMA), Polylactic-co-glycolic acid (PLGA), Polyamidoamine (PAMAM), and others remain exploited for their specific as well as shared characteristics in the rational delivery of anti-cancer agents. Variable nano size, attachment with tumor-specific proteins, responsiveness to stimuli and ability to deliver a wide range of molecules like drugs, antibodies and peptides are some of the achievements of polymeric nano-conjugates so far. Many such conjugates have shown potential clinically which has attracted the researchers and promoted further advancements of the technique. Apart from achievements the poly...
Journal of Controlled Release, 2011
Herein, new biodegradable star polymer-doxorubicin conjugates designed for passive tumor targeting were investigated, and their synthesis, physico-chemical characterization, drug release, biodegradation, biodistribution and in vivo anti-tumor efficacy are described. In the conjugates, the core formed by poly(amidoamine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds, which enabled intracellular pH-controlled drug release. The described synthesis facilitated the preparation of biodegradable polymer conjugates in a broad range of molecular weights (200-1000 g/mol) while still maintaining low polydispersity (~1.7). The polymer grafts were attached to the dendrimers through either stable amide bonds or enzymatically or reductively degradable spacers, which enabled intracellular degradation of the high-molecular-weight polymer carrier to excretable products. Biodegradability tests in suspensions of EL4 T-cell lymphoma cells showed that the rate of degradation was much faster for reductively degradable conjugates (close to completion within 24 h of incubation) than for conjugates linked via an enzymatically degradable oligopeptide GFLG sequence (slow degradation taking several days). This finding was likely due to the differences in steric hindrance in terms of the accessibility of the small molecule glutathione and the bulky enzyme cathepsin B to the polymer substrate. Regarding drug release, the conjugates were fairly stable in buffer at pH 7.4 (model of blood stream) but released doxorubicin under mild acidic conditions that model the tumor cell microenvironment. The star polymer-Dox conjugates exhibited significantly prolonged blood circulation and enhanced tumor accumulation in tumorbearing mice, indicating the important role of the EPR effect in its anti-cancer activity. The star polymer conjugates showed prominently higher in vivo anti-tumor activities than the free drug or linear polymer conjugate when tested in mice bearing EL4 T-cell lymphoma, with a significant number of long-term surviving (LTS). Based on the results, we conclude that a M w of HPMA copolymers of 200,000 to 600,000 g/mol is optimal for polymer carriers designed for the efficient passive targeting to solid tumors. In addition, an expressive therapydependent stimulation of the immune system was observed.